title: UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program.
abstract: The removal of histone H3 lysine27 (H3K27) trimethylation mark is important for the robust induction of many cell type-specific genes during differentiation. Here we show that UTX, a H3K27 demethylase, acts as a critical switch to promote a cardiac-specific gene program. UTX-deficient ESCs failed to develop heart-like rhythmic contractions under a cardiac differentiation condition. UTX-deficient mice show severe defects in heart development and embryonic lethality. We found that UTX is recruited to cardiac-specific enhancers by associating with core cardiac transcription factors and demethylates H3K27 residues in cardiac genes. In addition, UTX facilitates the recruitment of Brg1 to the cardiac-specific enhancers. Together, our data reveal key roles for UTX in a timely transition from poised to active chromatin in cardiac genes during heart development and a fundamental mechanism by which a H3K27 demethylase triggers tissue-specific chromatin changes.
authors.affiliation: Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005434:Flow Cytometry; D005804:Genes, Lethal; D006321:Heart / Q000196:embryology / Q000254:growth & development*; D056466:Histone Demethylases; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D008156:Luciferases; D056466:Histone Demethylases; C111778:Utx protein, mouse; C513194:Smarca4 protein, mouse; D004265:DNA Helicases