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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis
-
Blotting, Western
-
Cell Differentiation
-
Cell Lineage
-
Cell Proliferation
-
Chromatin / genetics*
-
Chromatin Immunoprecipitation
-
DNA Helicases / genetics
-
DNA Helicases / metabolism*
-
Embryonic Stem Cells / cytology
-
Embryonic Stem Cells / metabolism*
-
Enhancer Elements, Genetic / genetics*
-
Flow Cytometry
-
Genes, Lethal
-
Heart / embryology
-
Heart / growth & development*
-
Histone Demethylases
-
Histones / genetics
-
Histones / metabolism*
-
Immunoenzyme Techniques
-
Luciferases / metabolism
-
Methylation
-
Mice
-
Mice, Knockout
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism*
-
Nuclear Proteins / physiology*
-
RNA, Messenger / genetics
-
Real-Time Polymerase Chain Reaction
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
Substances
-
Chromatin
-
Histones
-
Nuclear Proteins
-
RNA, Messenger
-
Transcription Factors
-
Luciferases
-
Histone Demethylases
-
Utx protein, mouse
-
Smarca4 protein, mouse
-
DNA Helicases