title: Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity.
abstract: Self-renewal and pluripotency of embryonic stem cells (ESCs) are established by multiple regulatory pathways operating at several levels. The roles of histone demethylases (HDMs) in these programs are incompletely defined. We conducted a functional RNAi screen for HDMs and identified five potential HDMs essential for mouse ESC identity. In-depth analyses demonstrate that the closely related HDMs Jmjd2b and Jmjd2c are necessary for self-renewal of ESCs and induced pluripotent stem cell generation. Genome-wide occupancy studies reveal that Jmjd2b unique, Jmjd2c unique, and Jmjd2b-Jmjd2c common target sites belong to functionally separable Core, Polycomb repressive complex (PRC), and Myc regulatory modules, respectively. Jmjd2b and Nanog act through an interconnected regulatory loop, whereas Jmjd2c assists PRC2 in transcriptional repression. Thus, two HDMs of the same subclass exhibit distinct and combinatorial functions in control of the ESC state. Such complexity of HDM function reveals an aspect of multilayered transcriptional control.
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Partha Pratim
authors.initials: PP
authors.lastname: Das
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Semir
authors.initials: S
authors.lastname: Beyaz
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138.|Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114.
authors.forename: Eftychia
authors.initials: E
authors.lastname: Apostolou
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: De Los Angeles
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kassandra
authors.initials: K
authors.lastname: O'Brien
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer Marino
authors.initials: JM
authors.lastname: Atsma
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Damir
authors.initials: D
authors.lastname: Ljuboja
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Guoji
authors.initials: G
authors.lastname: Guo
authors.affiliation: Western Australian Institute for Medical Research, Royal Perth Hospital and School of Medicine and Pharmacology, The University of Western Australia, Nedlands 6009, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Woo
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.|Koç University, School of Medicine, Rumelifeneri Yolu, Sariyer 34450, Istanbul.
authors.forename: Tamer
authors.initials: T
authors.lastname: Onder
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.|Howard Hughes Medical Institute, Boston, MA 02115, USA.|Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138.
authors.forename: George
authors.initials: G
authors.lastname: Daley
authors.affiliation: Howard Hughes Medical Institute, Boston, MA 02115, USA.|Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138.|Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114.
authors.forename: Konrad
authors.initials: K
authors.lastname: Hochedlinger
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonghwan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.|Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology*; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000201:enzymology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C489428:Myc protein, mouse; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D056484:Jumonji Domain-Containing Histone Demethylases; C511781:Kdm4b protein, mouse; D063151:Polycomb Repressive Complex 2