UTX, a Histone H3-Lysine 27 Demethylase, Acts as a Critical Switch to Activate the Cardiac Developmental Program

• Published in: Developmental cell 2012-01, Vol.22 (1), p.25-37
• Main Authors: Lee, Seunghee, Lee, Jae W., Lee, Soo-Kyung
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell Lineage; Cell physiology; 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; Fundamental and applied biological sciences. Psychology; Genes, Lethal; Heart - embryology; Heart - growth & development; Histone Demethylases; Histones - genetics; Histones - metabolism; Immunoenzyme Techniques; Luciferases - metabolism; Methylation; Mice; Mice, Knockout; Molecular and cellular biology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.11.009

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. ► UTX is required for the activation of cardiac genes and heart development ► UTX associates with core cardiac transcription factors ► UTX binds to cardiac-specific enhancers and demethylates histone H3 on K27 ► UTX facilitates the recruitment of Brg1 to the cardiac-specific enhancers