title: An essential role for UTX in resolution and activation of bivalent promoters.
abstract: Trimethylated histone H3 lysine 27 (H3K27me3) is linked to gene silencing, whereas H3K4me3 is associated with gene activation. These two marks frequently co-occupy gene promoters, forming bivalent domains. Bivalency signifies repressed but activatable states of gene expression and can be resolved to active, H3K4me3-prevalent states during multiple cellular processes, including differentiation, development and epithelial mesenchymal transition. However, the molecular mechanism underlying bivalency resolution remains largely unknown. Here, we show that the H3K27 demethylase UTX (also called KDM6A) is required for the resolution and activation of numerous retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse embryonic stem cells (ESCs). Notably, UTX loss in mouse ESCs inhibited the RA-driven bivalency resolution and activation of most developmentally critical homeobox (Hox) a-d genes. The UTX-mediated resolution and activation of many bivalent Hox genes during mouse ESC differentiation were recapitulated during RA-driven differentiation of human NT2/D1 embryonal carcinoma cells. In support of the importance of UTX in bivalency resolution, Utx-null mouse ESCs and UTX-depleted NT2/D1 cells displayed defects in RA-driven cellular differentiation. Our results define UTX as a bivalency-resolving histone modifier necessary for stem cell differentiation.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Dhar
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sung-Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Institute for Academic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, The Methodist Hospital Research Institute, Houston, TX 77030, USA Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Kaifu
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Guangjing
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: WonKyung
authors.initials: W
authors.lastname: Oh
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kendra
authors.initials: K
authors.lastname: Allton
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ohad
authors.initials: O
authors.lastname: Gafni
authors.affiliation: Division of Neurooncology and Department of Neurosurgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, 158, Paryong-ro, Masan Hoiwon-Gu, Changwon, Gyeongsangnam-do, 630-723, Korea.
authors.forename: Young Zoon
authors.initials: YZ
authors.lastname: Kim
authors.affiliation: Institute for Academic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, The Methodist Hospital Research Institute, Houston, TX 77030, USA Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Alin S
authors.initials: AS
authors.lastname: Tomoiga
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Michelle Craig
authors.initials: MC
authors.lastname: Barton
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Hanna
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA zwang47@jhu.edu.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA WL1@bcm.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Cancer Biology Program,The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA mglee@mdanderson.org.
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005801:Genes, Homeobox; D056466:Histone Demethylases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D009687:Nuclear Proteins; D014212:Tretinoin; D056466:Histone Demethylases; C523998:KDM6A protein, human; C111778:Utx protein, mouse