Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment
Identifieur interne : 000230 ( Pmc/Checkpoint ); précédent : 000229; suivant : 000231Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment
Auteurs : Justin J. L. Wong [Australie] ; Dadi Gao [Australie] ; Trung V. Nguyen [Australie] ; Chau-To Kwok [Australie] ; Michelle Van Geldermalsen [Australie] ; Rob Middleton [Australie] ; Natalia Pinello [Australie] ; Annora Thoeng [Australie] ; Rajini Nagarajah [Australie] ; Jeff Holst [Australie] ; William Ritchie [Australie, France] ; John E. J. Rasko [Australie]Source :
- Nature Communications [ 2041-1723 ] ; 2017.
Abstract
While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression.
Url:
DOI: 10.1038/ncomms15134
PubMed: 28480880
PubMed Central: 5424149
Affiliations:
Links toward previous steps (curation, corpus...)
Links to Exploration step
PMC:5424149Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment</title><author><name sortKey="Wong, Justin J L" sort="Wong, Justin J L" uniqKey="Wong J" first="Justin J. L." last="Wong">Justin J. L. Wong</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Dadi" sort="Gao, Dadi" uniqKey="Gao D" first="Dadi" last="Gao">Dadi Gao</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Bioinformatics Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nguyen, Trung V" sort="Nguyen, Trung V" uniqKey="Nguyen T" first="Trung V." last="Nguyen">Trung V. Nguyen</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kwok, Chau To" sort="Kwok, Chau To" uniqKey="Kwok C" first="Chau-To" last="Kwok">Chau-To Kwok</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Geldermalsen, Michelle" sort="Van Geldermalsen, Michelle" uniqKey="Van Geldermalsen M" first="Michelle" last="Van Geldermalsen">Michelle Van Geldermalsen</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Origins of Cancer Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Middleton, Rob" sort="Middleton, Rob" uniqKey="Middleton R" first="Rob" last="Middleton">Rob Middleton</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Bioinformatics Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pinello, Natalia" sort="Pinello, Natalia" uniqKey="Pinello N" first="Natalia" last="Pinello">Natalia Pinello</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Thoeng, Annora" sort="Thoeng, Annora" uniqKey="Thoeng A" first="Annora" last="Thoeng">Annora Thoeng</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nagarajah, Rajini" sort="Nagarajah, Rajini" uniqKey="Nagarajah R" first="Rajini" last="Nagarajah">Rajini Nagarajah</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Holst, Jeff" sort="Holst, Jeff" uniqKey="Holst J" first="Jeff" last="Holst">Jeff Holst</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Origins of Cancer Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ritchie, William" sort="Ritchie, William" uniqKey="Ritchie W" first="William" last="Ritchie">William Ritchie</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Bioinformatics Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a6"><institution>CNRS, UMR 5203</institution>, 34094 Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rasko, John E J" sort="Rasko, John E J" uniqKey="Rasko J" first="John E. J." last="Rasko">John E. J. Rasko</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Cell and Molecular Therapies, Royal Prince Alfred Hospital</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28480880</idno><idno type="pmc">5424149</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424149</idno><idno type="RBID">PMC:5424149</idno><idno type="doi">10.1038/ncomms15134</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000790</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000790</idno><idno type="wicri:Area/Pmc/Curation">000789</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000789</idno><idno type="wicri:Area/Pmc/Checkpoint">000230</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000230</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment</title><author><name sortKey="Wong, Justin J L" sort="Wong, Justin J L" uniqKey="Wong J" first="Justin J. L." last="Wong">Justin J. L. Wong</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Dadi" sort="Gao, Dadi" uniqKey="Gao D" first="Dadi" last="Gao">Dadi Gao</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Bioinformatics Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nguyen, Trung V" sort="Nguyen, Trung V" uniqKey="Nguyen T" first="Trung V." last="Nguyen">Trung V. Nguyen</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kwok, Chau To" sort="Kwok, Chau To" uniqKey="Kwok C" first="Chau-To" last="Kwok">Chau-To Kwok</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Geldermalsen, Michelle" sort="Van Geldermalsen, Michelle" uniqKey="Van Geldermalsen M" first="Michelle" last="Van Geldermalsen">Michelle Van Geldermalsen</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Origins of Cancer Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Middleton, Rob" sort="Middleton, Rob" uniqKey="Middleton R" first="Rob" last="Middleton">Rob Middleton</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Bioinformatics Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pinello, Natalia" sort="Pinello, Natalia" uniqKey="Pinello N" first="Natalia" last="Pinello">Natalia Pinello</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Thoeng, Annora" sort="Thoeng, Annora" uniqKey="Thoeng A" first="Annora" last="Thoeng">Annora Thoeng</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nagarajah, Rajini" sort="Nagarajah, Rajini" uniqKey="Nagarajah R" first="Rajini" last="Nagarajah">Rajini Nagarajah</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Holst, Jeff" sort="Holst, Jeff" uniqKey="Holst J" first="Jeff" last="Holst">Jeff Holst</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Origins of Cancer Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ritchie, William" sort="Ritchie, William" uniqKey="Ritchie W" first="William" last="Ritchie">William Ritchie</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Bioinformatics Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a6"><institution>CNRS, UMR 5203</institution>, 34094 Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rasko, John E J" sort="Rasko, John E J" uniqKey="Rasko J" first="John E. J." last="Rasko">John E. J. Rasko</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Cell and Molecular Therapies, Royal Prince Alfred Hospital</institution>, Camperdown, New South Wales 2050,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Yap, K" uniqKey="Yap K">K. Yap</name></author><author><name sortKey="Lim, Z Q" uniqKey="Lim Z">Z. Q. Lim</name></author><author><name sortKey="Khandelia, P" uniqKey="Khandelia P">P. Khandelia</name></author><author><name sortKey="Friedman, B" uniqKey="Friedman B">B. Friedman</name></author><author><name sortKey="Makeyev, E V" uniqKey="Makeyev E">E. V. Makeyev</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wong J J L" uniqKey="Wong J J L">Wong J.J.-L.</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moore, M J" uniqKey="Moore M">M. J. Moore</name></author><author><name sortKey="Wang, Q" uniqKey="Wang Q">Q. Wang</name></author><author><name sortKey="Kennedy, C J" uniqKey="Kennedy C">C. J. Kennedy</name></author><author><name sortKey="Silver, P A" uniqKey="Silver P">P. A. Silver</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ergun, A" uniqKey="Ergun A">A. Ergun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shaked, I" uniqKey="Shaked I">I. Shaked</name></author><author><name sortKey="Zimmerman, G" uniqKey="Zimmerman G">G. Zimmerman</name></author><author><name sortKey="Soreq, H" uniqKey="Soreq H">H. Soreq</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Padgett, R A" uniqKey="Padgett R">R. A. Padgett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Edwards, C" uniqKey="Edwards C">C. Edwards</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pimentel, H" uniqKey="Pimentel H">H. Pimentel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Braunschweig, U" uniqKey="Braunschweig U">U. Braunschweig</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guo, R" uniqKey="Guo R">R. Guo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De La Mata, M" uniqKey="De La Mata M">M. de la Mata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maunakea, A K" uniqKey="Maunakea A">A. K. Maunakea</name></author><author><name sortKey="Chepelev, I" uniqKey="Chepelev I">I. Chepelev</name></author><author><name sortKey="Cui, K" uniqKey="Cui K">K. Cui</name></author><author><name sortKey="Zhao, K" uniqKey="Zhao K">K. Zhao</name></author><author><name sortKey="Intragenic, D N A" uniqKey="Intragenic D">D. N. A. Intragenic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shukla, S" uniqKey="Shukla S">S. Shukla</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gascard, P" uniqKey="Gascard P">P. Gascard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lin, S" uniqKey="Lin S">S. Lin</name></author><author><name sortKey="Coutinho Mansfield, G" uniqKey="Coutinho Mansfield G">G. Coutinho-Mansfield</name></author><author><name sortKey="Wang, D" uniqKey="Wang D">D. Wang</name></author><author><name sortKey="Pandit, S" uniqKey="Pandit S">S. Pandit</name></author><author><name sortKey="Fu, X D" uniqKey="Fu X">X.-D. Fu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fong, Y W" uniqKey="Fong Y">Y. W. Fong</name></author><author><name sortKey="Zhou, Q" uniqKey="Zhou Q">Q. Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lev Maor, G" uniqKey="Lev Maor G">G. Lev Maor</name></author><author><name sortKey="Yearim, A" uniqKey="Yearim A">A. Yearim</name></author><author><name sortKey="Ast, G" uniqKey="Ast G">G. Ast</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yearim, A" uniqKey="Yearim A">A. Yearim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Olins, A L" uniqKey="Olins A">A. L. Olins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Porfiri, E" uniqKey="Porfiri E">E. Porfiri</name></author><author><name sortKey="Hoffbrand, A" uniqKey="Hoffbrand A">A. Hoffbrand</name></author><author><name sortKey="Wickremasinghe, R" uniqKey="Wickremasinghe R">R. Wickremasinghe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lodhi, I J" uniqKey="Lodhi I">I. J. Lodhi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crawford, L J A" uniqKey="Crawford L">L. J. A. Crawford</name></author><author><name sortKey="Peake, R" uniqKey="Peake R">R. Peake</name></author><author><name sortKey="Price, S" uniqKey="Price S">S. Price</name></author><author><name sortKey="Morris, T C M" uniqKey="Morris T">T. C. M. Morris</name></author><author><name sortKey="Irvine, A E" uniqKey="Irvine A">A. E. Irvine</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jones, P A" uniqKey="Jones P">P. A. Jones</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li Byarlay, H" uniqKey="Li Byarlay H">H. Li-Byarlay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Laurent, L" uniqKey="Laurent L">L. Laurent</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gombart, A F" uniqKey="Gombart A">A. F. Gombart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nacken, W" uniqKey="Nacken W">W. Nacken</name></author><author><name sortKey="Roth, J" uniqKey="Roth J">J. Roth</name></author><author><name sortKey="Sorg, C" uniqKey="Sorg C">C. Sorg</name></author><author><name sortKey="Kerkhoff, C" uniqKey="Kerkhoff C">C. Kerkhoff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nathan, C" uniqKey="Nathan C">C. Nathan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, K T" uniqKey="Chan K">K. T. Chan</name></author><author><name sortKey="Creed, S J" uniqKey="Creed S">S. J. Creed</name></author><author><name sortKey="Bear, J E" uniqKey="Bear J">J. E. Bear</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Salerno, D M" uniqKey="Salerno D">D. M. Salerno</name></author><author><name sortKey="Tront, J S" uniqKey="Tront J">J. S. Tront</name></author><author><name sortKey="Hoffman, B" uniqKey="Hoffman B">B. Hoffman</name></author><author><name sortKey="Liebermann, D A" uniqKey="Liebermann D">D. A. Liebermann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gombart, A F" uniqKey="Gombart A">A. F. Gombart</name></author><author><name sortKey="Grewal, J" uniqKey="Grewal J">J. Grewal</name></author><author><name sortKey="Koeffler, H P" uniqKey="Koeffler H">H. P. Koeffler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baubec, T" uniqKey="Baubec T">T. Baubec</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baubec, T" uniqKey="Baubec T">T. Baubec</name></author><author><name sortKey="Ivanek, R" uniqKey="Ivanek R">R. Ivánek</name></author><author><name sortKey="Lienert, F" uniqKey="Lienert F">F. Lienert</name></author><author><name sortKey="Schubeler, D" uniqKey="Schubeler D">D. Schübeler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Young, J I" uniqKey="Young J">J. I. Young</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maxwell, S S" uniqKey="Maxwell S">S. S. Maxwell</name></author><author><name sortKey="Pelka, G J" uniqKey="Pelka G">G. J. Pelka</name></author><author><name sortKey="Tam, P P L" uniqKey="Tam P">P. P. L. Tam</name></author><author><name sortKey="El Osta, A" uniqKey="El Osta A">A. El-Osta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Long, S W" uniqKey="Long S">S. W. Long</name></author><author><name sortKey="Ooi, J Y Y" uniqKey="Ooi J">J. Y. Y. Ooi</name></author><author><name sortKey="Yau, P M" uniqKey="Yau P">P. M. Yau</name></author><author><name sortKey="Jones, P L" uniqKey="Jones P">P. L. Jones</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ghosh, R P" uniqKey="Ghosh R">R. P. Ghosh</name></author><author><name sortKey="Horowitz Scherer, R A" uniqKey="Horowitz Scherer R">R. A. Horowitz-Scherer</name></author><author><name sortKey="Nikitina, T" uniqKey="Nikitina T">T. Nikitina</name></author><author><name sortKey="Shlyakhtenko, L S" uniqKey="Shlyakhtenko L">L. S. Shlyakhtenko</name></author><author><name sortKey="Woodcock, C L" uniqKey="Woodcock C">C. L. Woodcock</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shepard, P J" uniqKey="Shepard P">P. J. Shepard</name></author><author><name sortKey="Hertel, K J" uniqKey="Hertel K">K. J. Hertel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dichmann, D S" uniqKey="Dichmann D">D. S. Dichmann</name></author><author><name sortKey="Walentek, P" uniqKey="Walentek P">P. Walentek</name></author><author><name sortKey="Harland, R M" uniqKey="Harland R">R. M. Harland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Best, A" uniqKey="Best A">A. Best</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hussein, S M I" uniqKey="Hussein S">S. M. I. Hussein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dvinge, H" uniqKey="Dvinge H">H. Dvinge</name></author><author><name sortKey="Bradley, R" uniqKey="Bradley R">R. Bradley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jung, H" uniqKey="Jung H">H. Jung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ni, T" uniqKey="Ni T">T. Ni</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wen, H" uniqKey="Wen H">H. Wen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marina, R J" uniqKey="Marina R">R. J. Marina</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tekpli, X" uniqKey="Tekpli X">X. Tekpli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song, C X" uniqKey="Song C">C.-X. Song</name></author><author><name sortKey="Yi, C" uniqKey="Yi C">C. Yi</name></author><author><name sortKey="He, C" uniqKey="He C">C. He</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, X" uniqKey="Yang X">X. Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Buckstein, R" uniqKey="Buckstein R">R. Buckstein</name></author><author><name sortKey="Yee, K" uniqKey="Yee K">K. Yee</name></author><author><name sortKey="Wells, R A" uniqKey="Wells R">R. A. Wells</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brown, R" uniqKey="Brown R">R. Brown</name></author><author><name sortKey="Curry, E" uniqKey="Curry E">E. Curry</name></author><author><name sortKey="Magnani, L" uniqKey="Magnani L">L. Magnani</name></author><author><name sortKey="Wilhelm Benartzi, C S" uniqKey="Wilhelm Benartzi C">C. S. Wilhelm-Benartzi</name></author><author><name sortKey="Borley, J" uniqKey="Borley J">J. Borley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Middleton, R" uniqKey="Middleton R">R. Middleton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wong, J" uniqKey="Wong J">J. Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mohammed, H" uniqKey="Mohammed H">H. Mohammed</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Challen, G A" uniqKey="Challen G">G. A. Challen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeong, M" uniqKey="Jeong M">M. Jeong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lund, K" uniqKey="Lund K">K. Lund</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trapnell, C" uniqKey="Trapnell C">C. Trapnell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, Y" uniqKey="Zhang Y">Y. Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dobin, A" uniqKey="Dobin A">A. Dobin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Audic, S" uniqKey="Audic S">S. Audic</name></author><author><name sortKey="Claverie, J M" uniqKey="Claverie J">J. M. Claverie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, D W" uniqKey="Huang D">D. W. Huang</name></author><author><name sortKey="Sherman, B T" uniqKey="Sherman B">B. T. Sherman</name></author><author><name sortKey="Lempicki, R A" uniqKey="Lempicki R">R. A. Lempicki</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28480880</article-id><article-id pub-id-type="pmc">5424149</article-id><article-id pub-id-type="pii">ncomms15134</article-id><article-id pub-id-type="doi">10.1038/ncomms15134</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Justin J. -L.</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Dadi</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a4">4</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Nguyen</surname><given-names>Trung V.</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Kwok</surname><given-names>Chau-To</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>van Geldermalsen</surname><given-names>Michelle</given-names></name><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Middleton</surname><given-names>Rob</given-names></name><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Pinello</surname><given-names>Natalia</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Thoeng</surname><given-names>Annora</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Nagarajah</surname><given-names>Rajini</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Holst</surname><given-names>Jeff</given-names></name><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a5">5</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-0377-9318</contrib-id></contrib><contrib contrib-type="author"><name><surname>Ritchie</surname><given-names>William</given-names></name><xref ref-type="corresp" rid="c2">b</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a4">4</xref><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Rasko</surname><given-names>John E. J.</given-names></name><xref ref-type="corresp" rid="c3">c</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a7">7</xref></contrib><aff id="a1"><label>1</label><institution>Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></aff><aff id="a2"><label>2</label><institution>Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></aff><aff id="a3"><label>3</label><institution>Sydney Medical School, University of Sydney</institution>, Sydney, New South Wales 2006,<country>Australia</country></aff><aff id="a4"><label>4</label><institution>Bioinformatics Laboratory, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></aff><aff id="a5"><label>5</label><institution>Origins of Cancer Program, Centenary Institute, University of Sydney</institution>, Camperdown, New South Wales 2050,<country>Australia</country></aff><aff id="a6"><label>6</label><institution>CNRS, UMR 5203</institution>, 34094 Montpellier,<country>France</country></aff><aff id="a7"><label>7</label><institution>Cell and Molecular Therapies, Royal Prince Alfred Hospital</institution>, Camperdown, New South Wales 2050,<country>Australia</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>j.wong@centenary.org.au</email></corresp><corresp id="c2"><label>b</label><email>william.ritchie@igf.cnrs.fr</email></corresp><corresp id="c3"><label>c</label><email>j.rasko@centenary.org.au</email></corresp><fn id="n1"><label>*</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>08</day><month>05</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>8</volume><elocation-id>15134</elocation-id><history><date date-type="received"><day>06</day><month>09</month><year>2016</year></date><date date-type="accepted"><day>02</day><month>03</month><year>2017</year></date></history><permissions><copyright-statement>Copyright © 2017, The Author(s)</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression.</p></abstract><abstract abstract-type="web-summary"><p>Intron retention is a conserved mechanism that controls gene expression but its regulation is poorly understood. Here, the authors provide evidence that DNA methylation regulates intron retention and find reduced MeCP2 occupancy and splicing factor recruitment near affected splice junctions.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>IR in myeloid cells is associated with lower DNA methylation levels near splice junctions and within retained introns.</title><p>(<bold>a</bold>) Average CpG methylation (CpG meth.) levels spanning ±100 bp from the 5′ and 3′ splice junctions, and from the middle of introns, in the DNA encoding non-retained (blue) and retained (red) introns in promyelocytes and granulocytes combined. Data were extended to −20 Mb and +20 Mb from the 5′ and 3′ splice junction respectively. <italic>t</italic>-test was used to determine significance at <italic>P</italic><0.05. (<bold>b</bold>) Examples from the IGV genome browser comparing IR levels in <italic>Lmnb1</italic> intron 5, <italic>Ngp</italic> intron 3 and <italic>S100a8</italic> intron 2 in promyelocytes (Prom.) and granulocytes (Gran.). (<bold>c</bold>) Average DNA methylation level at each CpG across <italic>Lmnb1</italic> intron 5, <italic>Ngp</italic> intron 3 and <italic>S100a8</italic> intron 2 and their flanking exons in promyelocytes and granulocytes as assessed using whole-genome bisulfite sequencing. A ±100 bp region from each splice junction, with reduced DNA methylation in granulocytes, is shaded in pink. (<bold>d</bold>) Confirmation of the results in <bold>c</bold> using clonal bisulfite sequencing. Each row represents a single-cloned PCR amplicon aligned to the exon–intron map shown above. Lollipops on exon–intron map indicate positions of CpG sites. Circles denote methylated (black) and unmethylated (white) CpGs. NS, not significant; Avg. meth., average DNA methylation levels.</p></caption><graphic xlink:href="ncomms15134-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>IR increases with reduced DNA methylation and increases following DNA methylation inhibition.</title><p>(<bold>a</bold>) Average CpG methylation levels spanning ±100 bp from the 5′ and 3′ splice junctions in the DNA encoding non-retained (blue) and retained (red) introns in primary mouse fibroblasts, mouse reprogrammed fibroblasts, human cell lines (H1, H9, HCT116 and IMR90) and primary human neuron progenitors. Data were extended to −20 Mb and +20 Mb from the 5′ and 3′ splice junctions, respectively. Paired <italic>t</italic>-tests were used to determine significance at <italic>P</italic><0.05. (<bold>b</bold>) Association between the IR ratio fold changes and their significance following double knockout of <italic>Dnmt3a</italic> and <italic>3b</italic> in primary mouse B cells and HSCs. Binomial test was used to determine the significance of bias between increased and decreased IR at <italic>P</italic><0.05. (<bold>c</bold>–<bold>f</bold>) Upper panel: clonal bisulfite sequencing displaying DNA methylation changes near splice junctions of <italic>Lmnb1</italic> intron 5, <italic>Ngp</italic> intron 3, <italic>Spata13</italic> intron 8 and <italic>S100a8</italic> intron 2 in MPRO cells following treatment with 3 or 7 μM 5-aza-2′deoxycytidine (5-Aza). Each row represents a single-cloned PCR amplicon aligned to the exon–intron map shown. Each lollipop on the map represents a CpG site. Black and white circles denote methylated and unmethylated CpGs respectively. Lower panel: IR levels determined by qRT-PCR for specific introns indicated in MPRO cells, with and without exposure to 5-Aza at 3 or 7 μM, and in the absence (–) or presence (+) of NMD inhibition via caffeine (CAF) treatment. Two-tailed <italic>t</italic>-test was used to determine significance at <italic>P</italic><0.05. Bars display mean±s.e.m. Independent qRT-PCR experiments were performed three times in triplicate (<italic>n</italic>=3). NS, not significant; Avg. meth., average DNA methylation levels.</p></caption><graphic xlink:href="ncomms15134-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>IR is associated with reduced MeCP2 binding near splice junctions.</title><p>(<bold>a</bold>) Average MeCP2 occupancy normalized against input as measured by ChIP-seq in promyelocytes and granulocytes combined. MeCP2 occupancy is displayed for regions spanning ±100 bp from the 5′ and 3′ splice junctions, and the middle of introns, in the DNA encoding non-retained (blue) and retained introns (red). Data were extended to −20 Mb and +20 Mb from the 5′ and 3′ splice junction respectively. <italic>t</italic>-tests were used to determine significance at <italic>P</italic><0.05. (<bold>b</bold>) Occupancy of MeCP2 near splice junctions of the DNA encoding introns with increased IR in granulocytes and controls measured by ChIP-qPCR. (<bold>c</bold>) ChIP-qPCR-measured occupancy of MeCP2 near splice junctions of the DNA encoding differentially retained introns of <italic>Lmnb1</italic> and <italic>Ngp</italic> pre- and post- 5-Aza-2′deoxycytidine treatment (5-Aza) in MPRO cells. <italic>Atf4</italic> intron 2 is included as a negative control. (<bold>d</bold>) Association between IR ratio fold changes and their significance following <italic>Mecp2</italic> knockdown in IMR90 cells or <italic>Mecp2</italic>- knockout in primary mouse cerebellum. Binomial test was used to determine the significance of bias between increased and decreased IR at <italic>P</italic><0.05. For each ChIP-qPCR experiment, a two-tailed Student's <italic>t</italic>-test was used to determine significance, denoted by *<italic>P</italic><0.05, **<italic>P</italic><0.001 and ns, not significant. Bars display mean±s.e.m. Independent ChIP-qPCR experiments were performed three to five times in triplicate.</p></caption><graphic xlink:href="ncomms15134-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>IR is associated with increased RNA Pol II occupancy that anti-correlates with MeCP2 density.</title><p>(<bold>a</bold>) Occupancies of MeCP2 and (<bold>b</bold>) Pol II Ser2p measured by ChIP-qPCR for retained introns and their flanking exons of <italic>Lmnb1</italic>, <italic>Ngp</italic> and <italic>S100a8</italic> in promyelocytes and granulocytes. (<bold>c</bold>) ChIP-qPCR analyses of MeCP2 and (<bold>d</bold>) Pol II Ser2p occupancies measured for non-retained introns: <italic>Lmnb1</italic> intron 3, <italic>Smarcd1</italic> intron 9, <italic>Tbp</italic> intron 5 and their flanking exons. P1–P8 indicate positions of PCR amplicons within each region. For each ChIP-qPCR experiment, a two-tailed Student's <italic>t</italic>-test was used to determine significance, denoted by *<italic>P</italic><0.05, **<italic>P</italic><0.001 and NS, not significant. Dots and bars display mean±s.e.m. Independent ChIP-qPCR experiments were performed three to five times in triplicate.</p></caption><graphic xlink:href="ncomms15134-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Reduced MeCP2-mediated recruitment of the splicing factor Tra2b promotes IR.</title><p>(<bold>a</bold>) Schematic of the RIME assay to identify MeCP2 binding partners in normal promyelocytes (Prom.) and granulocytes (Gran.). (<bold>b</bold>) Venn diagram showing proteins that bind to MeCP2 in promyelocytes and/or granulocytes. MeCP2 bound splicing factors enriched in promyelocytes are listed. (<bold>c</bold>) Occupancies of MeCP2 and (<bold>d</bold>) Tra2b in the coding region of <italic>Malat1</italic> and <italic>Tra2a</italic> in promyelocytes and granulocytes measured by RNA-IP followed by qRT-PCR. (<bold>e</bold>) Occupancies of MeCP2 and (<bold>f</bold>) Tra2b near splice junctions of <italic>Lmnb1</italic> intron 5, <italic>Ngp</italic> intron 3 and <italic>S100a8</italic> intron 2 in normal promyelocytes compared to granulocytes by RNA-IP. (<bold>g</bold>) Occupancies of MeCP2 and (<bold>h</bold>) Tra2b near splice junctions of constitutively spliced <italic>Smarcd1</italic> intron 9 and <italic>TBP</italic> intron 5 in normal promyelocytes compared to granulocytes by RNA-IP. (<bold>i</bold>) Occupancies of MeCP2 and Tra2b near splice junctions of <italic>Lmnb1</italic> intron 5, <italic>Ngp</italic> intron 3 and <italic>S100a8</italic> intron 2, <italic>Smarcd1</italic> intron 9 and <italic>TBP</italic> intron 5 in normal promyelocytes compared to granulocytes by RNA-IP-reIP. Levels of occupancies are shown relative to background inferred by sequential Tra2b-IgG RNA-IP controls. A two-tailed <italic>t</italic>-test was used to determine significance, denoted by *<italic>P</italic><0.05, **<italic>P</italic><0.001 and NS, not significant. Dots and bars display mean±s.e.m. Independent qRT-PCR experiments were performed three to five times in triplicate.</p></caption><graphic xlink:href="ncomms15134-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Proposed model of IR regulation.</title><p>IR occurs via less efficient splicing factor (e.g. Tra2b) recruitment consequent to reduced DNA-methylation-mediated MeCP2 binding.</p></caption><graphic xlink:href="ncomms15134-f6"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Australie</li><li>France</li></country></list><tree><country name="Australie"><noRegion><name sortKey="Wong, Justin J L" sort="Wong, Justin J L" uniqKey="Wong J" first="Justin J. L." last="Wong">Justin J. L. Wong</name></noRegion><name sortKey="Gao, Dadi" sort="Gao, Dadi" uniqKey="Gao D" first="Dadi" last="Gao">Dadi Gao</name><name sortKey="Gao, Dadi" sort="Gao, Dadi" uniqKey="Gao D" first="Dadi" last="Gao">Dadi Gao</name><name sortKey="Gao, Dadi" sort="Gao, Dadi" uniqKey="Gao D" first="Dadi" last="Gao">Dadi Gao</name><name sortKey="Holst, Jeff" sort="Holst, Jeff" uniqKey="Holst J" first="Jeff" last="Holst">Jeff Holst</name><name sortKey="Holst, Jeff" sort="Holst, Jeff" uniqKey="Holst J" first="Jeff" last="Holst">Jeff Holst</name><name sortKey="Kwok, Chau To" sort="Kwok, Chau To" uniqKey="Kwok C" first="Chau-To" last="Kwok">Chau-To Kwok</name><name sortKey="Kwok, Chau To" sort="Kwok, Chau To" uniqKey="Kwok C" first="Chau-To" last="Kwok">Chau-To Kwok</name><name sortKey="Kwok, Chau To" sort="Kwok, Chau To" uniqKey="Kwok C" first="Chau-To" last="Kwok">Chau-To Kwok</name><name sortKey="Middleton, Rob" sort="Middleton, Rob" uniqKey="Middleton R" first="Rob" last="Middleton">Rob Middleton</name><name sortKey="Middleton, Rob" sort="Middleton, Rob" uniqKey="Middleton R" first="Rob" last="Middleton">Rob Middleton</name><name sortKey="Nagarajah, Rajini" sort="Nagarajah, Rajini" uniqKey="Nagarajah R" first="Rajini" last="Nagarajah">Rajini Nagarajah</name><name sortKey="Nagarajah, Rajini" sort="Nagarajah, Rajini" uniqKey="Nagarajah R" first="Rajini" last="Nagarajah">Rajini Nagarajah</name><name sortKey="Nguyen, Trung V" sort="Nguyen, Trung V" uniqKey="Nguyen T" first="Trung V." last="Nguyen">Trung V. Nguyen</name><name sortKey="Nguyen, Trung V" sort="Nguyen, Trung V" uniqKey="Nguyen T" first="Trung V." last="Nguyen">Trung V. Nguyen</name><name sortKey="Nguyen, Trung V" sort="Nguyen, Trung V" uniqKey="Nguyen T" first="Trung V." last="Nguyen">Trung V. Nguyen</name><name sortKey="Pinello, Natalia" sort="Pinello, Natalia" uniqKey="Pinello N" first="Natalia" last="Pinello">Natalia Pinello</name><name sortKey="Pinello, Natalia" sort="Pinello, Natalia" uniqKey="Pinello N" first="Natalia" last="Pinello">Natalia Pinello</name><name sortKey="Pinello, Natalia" sort="Pinello, Natalia" uniqKey="Pinello N" first="Natalia" last="Pinello">Natalia Pinello</name><name sortKey="Rasko, John E J" sort="Rasko, John E J" uniqKey="Rasko J" first="John E. J." last="Rasko">John E. J. Rasko</name><name sortKey="Rasko, John E J" sort="Rasko, John E J" uniqKey="Rasko J" first="John E. J." last="Rasko">John E. J. Rasko</name><name sortKey="Rasko, John E J" sort="Rasko, John E J" uniqKey="Rasko J" first="John E. J." last="Rasko">John E. J. Rasko</name><name sortKey="Ritchie, William" sort="Ritchie, William" uniqKey="Ritchie W" first="William" last="Ritchie">William Ritchie</name><name sortKey="Ritchie, William" sort="Ritchie, William" uniqKey="Ritchie W" first="William" last="Ritchie">William Ritchie</name><name sortKey="Ritchie, William" sort="Ritchie, William" uniqKey="Ritchie W" first="William" last="Ritchie">William Ritchie</name><name sortKey="Thoeng, Annora" sort="Thoeng, Annora" uniqKey="Thoeng A" first="Annora" last="Thoeng">Annora Thoeng</name><name sortKey="Thoeng, Annora" sort="Thoeng, Annora" uniqKey="Thoeng A" first="Annora" last="Thoeng">Annora Thoeng</name><name sortKey="Van Geldermalsen, Michelle" sort="Van Geldermalsen, Michelle" uniqKey="Van Geldermalsen M" first="Michelle" last="Van Geldermalsen">Michelle Van Geldermalsen</name><name sortKey="Van Geldermalsen, Michelle" sort="Van Geldermalsen, Michelle" uniqKey="Van Geldermalsen M" first="Michelle" last="Van Geldermalsen">Michelle Van Geldermalsen</name><name sortKey="Wong, Justin J L" sort="Wong, Justin J L" uniqKey="Wong J" first="Justin J. L." last="Wong">Justin J. L. Wong</name><name sortKey="Wong, Justin J L" sort="Wong, Justin J L" uniqKey="Wong J" first="Justin J. L." last="Wong">Justin J. L. Wong</name></country><country name="France"><noRegion><name sortKey="Ritchie, William" sort="Ritchie, William" uniqKey="Ritchie W" first="William" last="Ritchie">William Ritchie</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000230 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd -nk 000230 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Pmc
|étape= Checkpoint
|type= RBID
|clé= PMC:5424149
|texte= Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/RBID.i -Sk "pubmed:28480880" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd \
| NlmPubMed2Wicri -a AustralieFrV1
| This area was generated with Dilib version V0.6.33. |  |