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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Relationship of DNA Methylation and Gene Expression in Idiopathic Pulmonary Fibrosis</title><author><name sortKey="Yang, Ivana V" sort="Yang, Ivana V" uniqKey="Yang I" first="Ivana V." last="Yang">Ivana V. Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Pedersen, Brent S" sort="Pedersen, Brent S" uniqKey="Pedersen B" first="Brent S." last="Pedersen">Brent S. Pedersen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rabinovich, Einat" sort="Rabinovich, Einat" uniqKey="Rabinovich E" first="Einat" last="Rabinovich">Einat Rabinovich</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Hennessy, Corinne E" sort="Hennessy, Corinne E" uniqKey="Hennessy C" first="Corinne E." last="Hennessy">Corinne E. Hennessy</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Davidson, Elizabeth J" sort="Davidson, Elizabeth J" uniqKey="Davidson E" first="Elizabeth J." last="Davidson">Elizabeth J. Davidson</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Murphy, Elissa" sort="Murphy, Elissa" uniqKey="Murphy E" first="Elissa" last="Murphy">Elissa Murphy</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Guardela, Brenda Juan" sort="Guardela, Brenda Juan" uniqKey="Guardela B" first="Brenda Juan" last="Guardela">Brenda Juan Guardela</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Tedrow, John R" sort="Tedrow, John R" uniqKey="Tedrow J" first="John R." last="Tedrow">John R. Tedrow</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Yingze" sort="Zhang, Yingze" uniqKey="Zhang Y" first="Yingze" last="Zhang">Yingze Zhang</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Singh, Mandal K" sort="Singh, Mandal K" uniqKey="Singh M" first="Mandal K." last="Singh">Mandal K. Singh</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Correll, Mick" sort="Correll, Mick" uniqKey="Correll M" first="Mick" last="Correll">Mick Correll</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Schwarz, Marvin I" sort="Schwarz, Marvin I" uniqKey="Schwarz M" first="Marvin I." last="Schwarz">Marvin I. Schwarz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Geraci, Mark" sort="Geraci, Mark" uniqKey="Geraci M" first="Mark" last="Geraci">Mark Geraci</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Sciurba, Frank C" sort="Sciurba, Frank C" uniqKey="Sciurba F" first="Frank C." last="Sciurba">Frank C. Sciurba</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Quackenbush, John" sort="Quackenbush, John" uniqKey="Quackenbush J" first="John" last="Quackenbush">John Quackenbush</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Spira, Avrum" sort="Spira, Avrum" uniqKey="Spira A" first="Avrum" last="Spira">Avrum Spira</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Kaminski, Naftali" sort="Kaminski, Naftali" uniqKey="Kaminski N" first="Naftali" last="Kaminski">Naftali Kaminski</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Schwartz, David A" sort="Schwartz, David A" uniqKey="Schwartz D" first="David A." last="Schwartz">David A. Schwartz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25333685</idno><idno type="pmc">4315819</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315819</idno><idno type="RBID">PMC:4315819</idno><idno type="doi">10.1164/rccm.201408-1452OC</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000873</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000873</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Relationship of DNA Methylation and Gene Expression in Idiopathic Pulmonary Fibrosis</title><author><name sortKey="Yang, Ivana V" sort="Yang, Ivana V" uniqKey="Yang I" first="Ivana V." last="Yang">Ivana V. Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Pedersen, Brent S" sort="Pedersen, Brent S" uniqKey="Pedersen B" first="Brent S." last="Pedersen">Brent S. Pedersen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rabinovich, Einat" sort="Rabinovich, Einat" uniqKey="Rabinovich E" first="Einat" last="Rabinovich">Einat Rabinovich</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Hennessy, Corinne E" sort="Hennessy, Corinne E" uniqKey="Hennessy C" first="Corinne E." last="Hennessy">Corinne E. Hennessy</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Davidson, Elizabeth J" sort="Davidson, Elizabeth J" uniqKey="Davidson E" first="Elizabeth J." last="Davidson">Elizabeth J. Davidson</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Murphy, Elissa" sort="Murphy, Elissa" uniqKey="Murphy E" first="Elissa" last="Murphy">Elissa Murphy</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Guardela, Brenda Juan" sort="Guardela, Brenda Juan" uniqKey="Guardela B" first="Brenda Juan" last="Guardela">Brenda Juan Guardela</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Tedrow, John R" sort="Tedrow, John R" uniqKey="Tedrow J" first="John R." last="Tedrow">John R. Tedrow</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Yingze" sort="Zhang, Yingze" uniqKey="Zhang Y" first="Yingze" last="Zhang">Yingze Zhang</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Singh, Mandal K" sort="Singh, Mandal K" uniqKey="Singh M" first="Mandal K." last="Singh">Mandal K. Singh</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Correll, Mick" sort="Correll, Mick" uniqKey="Correll M" first="Mick" last="Correll">Mick Correll</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Schwarz, Marvin I" sort="Schwarz, Marvin I" uniqKey="Schwarz M" first="Marvin I." last="Schwarz">Marvin I. Schwarz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Geraci, Mark" sort="Geraci, Mark" uniqKey="Geraci M" first="Mark" last="Geraci">Mark Geraci</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Sciurba, Frank C" sort="Sciurba, Frank C" uniqKey="Sciurba F" first="Frank C." last="Sciurba">Frank C. Sciurba</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Quackenbush, John" sort="Quackenbush, John" uniqKey="Quackenbush J" first="John" last="Quackenbush">John Quackenbush</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Spira, Avrum" sort="Spira, Avrum" uniqKey="Spira A" first="Avrum" last="Spira">Avrum Spira</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Kaminski, Naftali" sort="Kaminski, Naftali" uniqKey="Kaminski N" first="Naftali" last="Kaminski">Naftali Kaminski</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Schwartz, David A" sort="Schwartz, David A" uniqKey="Schwartz D" first="David A." last="Schwartz">David A. Schwartz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Respiratory and Critical Care Medicine</title><idno type="ISSN">1073-449X</idno><idno type="eISSN">1535-4970</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><bold>Rationale:</bold> Idiopathic pulmonary fibrosis (IPF) is an untreatable and often fatal lung disease that is increasing in prevalence and is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control gene expression and are likely to regulate the IPF transcriptome.</p><p><bold>Objectives:</bold> To identify methylation marks that modify gene expression in IPF lung.</p><p><bold>Methods:</bold> We assessed DNA methylation (comprehensive high-throughput arrays for relative methylation arrays [CHARM]) and gene expression (Agilent gene expression arrays) in 94 patients with IPF and 67 control subjects, and performed integrative genomic analyses to define methylation–gene expression relationships in IPF lung. We validated methylation changes by a targeted analysis (Epityper), and performed functional validation of one of the genes identified by our analysis.</p><p><bold>Measurements and Main Results:</bold> We identified 2,130 differentially methylated regions (DMRs; <5% false discovery rate), of which 738 are associated with significant changes in gene expression and enriched for expected inverse relationship between methylation and expression (<italic>P</italic> < 2.2 × 10<sup>−16</sup>). We validated 13/15 DMRs by targeted analysis of methylation. Methylation–expression quantitative trait loci (methyl-eQTL) identified methylation marks that control <italic>cis</italic> and <italic>trans</italic> gene expression, with an enrichment for <italic>cis</italic> relationships (<italic>P</italic> < 2.2 × 10<sup>−16</sup>). We found five <italic>trans</italic> methyl-eQTLs where a methylation change at a single DMR is associated with transcriptional changes in a substantial number of genes; four of these DMRs are near transcription factors (castor zinc finger 1 [CASZ1], FOXC1, MXD4, and ZDHHC4). We studied the <italic>in vitro</italic> effects of change in CASZ1 expression and validated its role in regulation of target genes in the methyl-eQTL.</p><p><bold>Conclusions:</bold> These results suggest that DNA methylation may be involved in the pathogenesis of IPF.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Respir Crit Care Med</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Respir. Crit. Care Med</journal-id><journal-id journal-id-type="publisher-id">ajrccm</journal-id><journal-title-group><journal-title>American Journal of Respiratory and Critical Care Medicine</journal-title></journal-title-group><issn pub-type="ppub">1073-449X</issn><issn pub-type="epub">1535-4970</issn><publisher><publisher-name>American Thoracic Society</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25333685</article-id><article-id pub-id-type="pmc">4315819</article-id><article-id pub-id-type="publisher-manuscript">201408-1452OC</article-id><article-id pub-id-type="doi">10.1164/rccm.201408-1452OC</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject><subj-group><subject>Interstitial Lung Disease</subject></subj-group></subj-group></article-categories><title-group><article-title>Relationship of DNA Methylation and Gene Expression in Idiopathic Pulmonary Fibrosis</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Yang</surname><given-names>Ivana V.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pedersen</surname><given-names>Brent S.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rabinovich</surname><given-names>Einat</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hennessy</surname><given-names>Corinne E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Davidson</surname><given-names>Elizabeth J.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Murphy</surname><given-names>Elissa</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guardela</surname><given-names>Brenda Juan</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tedrow</surname><given-names>John R.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Yingze</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Singh</surname><given-names>Mandal K.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Correll</surname><given-names>Mick</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schwarz</surname><given-names>Marvin I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Geraci</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sciurba</surname><given-names>Frank C.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Quackenbush</surname><given-names>John</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Spira</surname><given-names>Avrum</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kaminski</surname><given-names>Naftali</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schwartz</surname><given-names>David A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><aff id="aff1"><label><sup>1</sup></label>Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado</aff><aff id="aff2"><label><sup>2</sup></label>Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado</aff><aff id="aff3"><label><sup>3</sup></label>Simmons Center for Interstitial Lung Disease and Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania</aff><aff id="aff4"><label><sup>4</sup></label>Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut</aff><aff id="aff5"><label><sup>5</sup></label>Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts; and</aff><aff id="aff6"><label><sup>6</sup></label>Department of Medicine, Boston University School of Medicine, Boston, Massachusetts</aff></contrib-group><author-notes><corresp>Correspondence and requests for reprints should be addressed to Ivana V. Yang, Ph.D., University of Colorado Denver, 12700 East 19th Avenue, 8611, Aurora, CO 80045. E-mail: <email xlink:href="ivana.yang@ucdenver.edu">ivana.yang@ucdenver.edu</email></corresp></author-notes><pub-date pub-type="epub-ppub"><day>1</day><month>12</month><year>2014</year><pmc-comment>string-date: December 1, 2014</pmc-comment>
</pub-date><pmc-comment>Fake epub and ppub dates generated by PMC from publisher
pub-date/@pub-type='epub-ppub' </pmc-comment>
<pub-date pub-type="epub"><day>1</day><month>12</month><year>2014</year><pmc-comment>string-date: December 1, 2014</pmc-comment>
</pub-date><pub-date pub-type="ppub"><day>1</day><month>12</month><year>2014</year><pmc-comment>string-date: December 1, 2014</pmc-comment>
</pub-date><volume>190</volume><issue>11</issue><fpage>1263</fpage><lpage>1272</lpage><history><date date-type="received"><day>11</day><month>8</month><year>2014</year></date><date date-type="accepted"><day>17</day><month>10</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2014 by the American Thoracic Society</copyright-statement><copyright-year>2014</copyright-year></permissions><self-uri content-type="pdf" xlink:href="rccm.201408-1452OC.pdf"></self-uri><abstract><p><bold>Rationale:</bold> Idiopathic pulmonary fibrosis (IPF) is an untreatable and often fatal lung disease that is increasing in prevalence and is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control gene expression and are likely to regulate the IPF transcriptome.</p><p><bold>Objectives:</bold> To identify methylation marks that modify gene expression in IPF lung.</p><p><bold>Methods:</bold> We assessed DNA methylation (comprehensive high-throughput arrays for relative methylation arrays [CHARM]) and gene expression (Agilent gene expression arrays) in 94 patients with IPF and 67 control subjects, and performed integrative genomic analyses to define methylation–gene expression relationships in IPF lung. We validated methylation changes by a targeted analysis (Epityper), and performed functional validation of one of the genes identified by our analysis.</p><p><bold>Measurements and Main Results:</bold> We identified 2,130 differentially methylated regions (DMRs; <5% false discovery rate), of which 738 are associated with significant changes in gene expression and enriched for expected inverse relationship between methylation and expression (<italic>P</italic> < 2.2 × 10<sup>−16</sup>). We validated 13/15 DMRs by targeted analysis of methylation. Methylation–expression quantitative trait loci (methyl-eQTL) identified methylation marks that control <italic>cis</italic> and <italic>trans</italic> gene expression, with an enrichment for <italic>cis</italic> relationships (<italic>P</italic> < 2.2 × 10<sup>−16</sup>). We found five <italic>trans</italic> methyl-eQTLs where a methylation change at a single DMR is associated with transcriptional changes in a substantial number of genes; four of these DMRs are near transcription factors (castor zinc finger 1 [CASZ1], FOXC1, MXD4, and ZDHHC4). We studied the <italic>in vitro</italic> effects of change in CASZ1 expression and validated its role in regulation of target genes in the methyl-eQTL.</p><p><bold>Conclusions:</bold> These results suggest that DNA methylation may be involved in the pathogenesis of IPF.</p></abstract><kwd-group><title>Keywords</title><kwd>DNA methylation</kwd><kwd>gene expression</kwd><kwd>pulmonary fibrosis</kwd><kwd>quantitative trait</kwd><kwd>mapping</kwd></kwd-group><counts><fig-count count="4"></fig-count><table-count count="1"></table-count><page-count count="10"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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