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Article: Transcriptional genomics associates FOX transcription factors with human heart failure

TitleTranscriptional genomics associates FOX transcription factors with human heart failure
Authors
Issue Date2006
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.org
Citation
Circulation, 2006, v. 114 n. 12, p. 1269-1276 How to Cite?
AbstractBACKGROUND - Specific transcription factors (TFs) modulate cardiac gene expression in murine models of heart failure, but their relevance in human subjects remains untested. We developed and applied a computational approach called transcriptional genomics to test the hypothesis that a discrete set of cardiac TFs is associated with human heart failure. METHODS AND RESULTS - RNA isolates from failing (n=196) and nonfailing (n=16) human hearts were hybridized with Affymetrix HU133A arrays, and differentially expressed heart failure genes were determined. TF binding sites overrepresented in the -5-kb promoter sequences of these heart failure genes were then determined with the use of public genome sequence databases. Binding sites for TFs identified in murine heart failure models (MEF2, NKX, NF-AT, and GATA) were significantly overrepresented in promoters of human heart failure genes (P<0.002; false discovery rate 2% to 4%). In addition, binding sites for FOX TFs showed substantial overrepresentation in both advanced human and early murine heart failure (P<0.002 and false discovery rate <4% for each). A role for FOX TFs was supported further by expression of FOXC1, C2, P1, P4, and O1A in failing human cardiac myocytes at levels similar to established hypertrophic TFs and by abundant FOXP1 protein in failing human cardiac myocyte nuclei. CONCLUSIONS - Our results provide the first evidence that specific TFs identified in murine models (MEF2, NKX, NFAT, and GATA) are associated with human heart failure. Moreover, these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis. These findings provide a crucial link between animal models and human disease and suggest a specific role for FOX signaling in modulating the hypertrophic response of the heart to stress in humans. © 2006 American Heart Association, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/147546
ISSN
2015 Impact Factor: 17.047
2015 SCImago Journal Rankings: 7.853
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHannenhalli, Sen_US
dc.contributor.authorPutt, MEen_US
dc.contributor.authorGilmore, JMen_US
dc.contributor.authorWang, Jen_US
dc.contributor.authorParmacek, MSen_US
dc.contributor.authorEpstein, JAen_US
dc.contributor.authorMorrisey, EEen_US
dc.contributor.authorMargulies, KBen_US
dc.contributor.authorCappola, TPen_US
dc.date.accessioned2012-05-29T06:04:30Z-
dc.date.available2012-05-29T06:04:30Z-
dc.date.issued2006en_US
dc.identifier.citationCirculation, 2006, v. 114 n. 12, p. 1269-1276en_US
dc.identifier.issn0009-7322en_US
dc.identifier.urihttp://hdl.handle.net/10722/147546-
dc.description.abstractBACKGROUND - Specific transcription factors (TFs) modulate cardiac gene expression in murine models of heart failure, but their relevance in human subjects remains untested. We developed and applied a computational approach called transcriptional genomics to test the hypothesis that a discrete set of cardiac TFs is associated with human heart failure. METHODS AND RESULTS - RNA isolates from failing (n=196) and nonfailing (n=16) human hearts were hybridized with Affymetrix HU133A arrays, and differentially expressed heart failure genes were determined. TF binding sites overrepresented in the -5-kb promoter sequences of these heart failure genes were then determined with the use of public genome sequence databases. Binding sites for TFs identified in murine heart failure models (MEF2, NKX, NF-AT, and GATA) were significantly overrepresented in promoters of human heart failure genes (P<0.002; false discovery rate 2% to 4%). In addition, binding sites for FOX TFs showed substantial overrepresentation in both advanced human and early murine heart failure (P<0.002 and false discovery rate <4% for each). A role for FOX TFs was supported further by expression of FOXC1, C2, P1, P4, and O1A in failing human cardiac myocytes at levels similar to established hypertrophic TFs and by abundant FOXP1 protein in failing human cardiac myocyte nuclei. CONCLUSIONS - Our results provide the first evidence that specific TFs identified in murine models (MEF2, NKX, NFAT, and GATA) are associated with human heart failure. Moreover, these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis. These findings provide a crucial link between animal models and human disease and suggest a specific role for FOX signaling in modulating the hypertrophic response of the heart to stress in humans. © 2006 American Heart Association, Inc.en_US
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.orgen_US
dc.relation.ispartofCirculationen_US
dc.subject.meshAdulten_US
dc.subject.meshAgeden_US
dc.subject.meshAnimalsen_US
dc.subject.meshCardiac Output, Low - Etiology - Geneticsen_US
dc.subject.meshDna - Geneticsen_US
dc.subject.meshForkhead Transcription Factors - Genetics - Physiologyen_US
dc.subject.meshGene Expression Regulationen_US
dc.subject.meshGenomicsen_US
dc.subject.meshHumansen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred Strainsen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshOligonucleotide Array Sequence Analysisen_US
dc.subject.meshRna - Geneticsen_US
dc.subject.meshSequence Analysis, Dna - Methodsen_US
dc.subject.meshTranscription, Genetic - Geneticsen_US
dc.titleTranscriptional genomics associates FOX transcription factors with human heart failureen_US
dc.typeArticleen_US
dc.identifier.emailWang, J:junwen@hkucc.hku.hken_US
dc.identifier.authorityWang, J=rp00280en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1161/CIRCULATIONAHA.106.632430en_US
dc.identifier.pmid16952980-
dc.identifier.scopuseid_2-s2.0-33748745399en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33748745399&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume114en_US
dc.identifier.issue12en_US
dc.identifier.spage1269en_US
dc.identifier.epage1276en_US
dc.identifier.isiWOS:000240556700008-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHannenhalli, S=6603889650en_US
dc.identifier.scopusauthoridPutt, ME=7005311984en_US
dc.identifier.scopusauthoridGilmore, JM=7102107277en_US
dc.identifier.scopusauthoridWang, J=8950599500en_US
dc.identifier.scopusauthoridParmacek, MS=7006655564en_US
dc.identifier.scopusauthoridEpstein, JA=7401891704en_US
dc.identifier.scopusauthoridMorrisey, EE=7003661185en_US
dc.identifier.scopusauthoridMargulies, KB=7005687184en_US
dc.identifier.scopusauthoridCappola, TP=6602787960en_US

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