title: Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network.
abstract: The embryonic stem (ES) cell transcriptional and chromatin-modifying networks are critical for self-renewal maintenance. However, it remains unclear whether these networks functionally interact and, if so, what factors mediate such interactions. Here, we show that WD repeat domain 5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a regulator of ES cell self-renewal. We demonstrate that Wdr5, an "effector" of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. Genome-wide protein localization and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. The Oct4-Sox2-Nanog circuitry and trxG cooperate in activating transcription of key self-renewal regulators, and furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. We propose an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming.
authors.affiliation: Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA. yen-sin.ang@mssm.edu
authors.forename: Yen-Sin
authors.initials: YS
authors.lastname: Ang
authors.forename: Su-Yi
authors.initials: SY
authors.lastname: Tsai
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Monk
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.forename: Kajan
authors.initials: K
authors.lastname: Ratnakumar
authors.forename: Junjun
authors.initials: J
authors.lastname: Ding
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Ge
authors.forename: Henia
authors.initials: H
authors.lastname: Darr
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Rendl
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
authors.forename: Christoph
authors.initials: C
authors.lastname: Schaniel
authors.forename: Ihor R
authors.initials: IR
authors.lastname: Lemischka
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D053263:Gene Regulatory Networks; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008745:Methylation; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D050814:Octamer Transcription Factor-3; D011506:Proteins; C443118:Wdr5 protein, mouse; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse