title: A poised chromatin platform for TGF-β access to master regulators.
abstract: Specific chromatin marks keep master regulators of differentiation silent yet poised for activation by extracellular signals. We report that nodal TGF-β signals use the poised histone mark H3K9me3 to trigger differentiation of mammalian embryonic stem cells. Nodal receptors induce the formation of companion Smad4-Smad2/3 and TRIM33-Smad2/3 complexes. The PHD-Bromo cassette of TRIM33 facilitates binding of TRIM33-Smad2/3 to H3K9me3 and H3K18ac on the promoters of mesendoderm regulators Gsc and Mixl1. The crystal structure of this cassette, bound to histone H3 peptides, illustrates that PHD recognizes K9me3, and Bromo binds an adjacent K18ac. The interaction between TRIM33-Smad2/3 and H3K9me3 displaces the chromatin-compacting factor HP1γ, making nodal response elements accessible to Smad4-Smad2/3 for Pol II recruitment. In turn, Smad4 increases K18 acetylation to augment TRIM33-Smad2/3 binding. Thus, nodal effectors use the H3K9me3 mark as a platform to switch master regulators of stem cell differentiation from the poised to the active state.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Qiaoran
authors.initials: Q
authors.lastname: Xi
authors.forename: Zhanxin
authors.initials: Z
authors.lastname: Wang
authors.forename: Alexia-Ileana
authors.initials: AI
authors.lastname: Zaromytidou
authors.forename: Xiang H-F
authors.initials: XH
authors.lastname: Zhang
authors.forename: Lai-Fong
authors.initials: LF
authors.lastname: Chow-Tsang
authors.forename: Jing X
authors.initials: JX
authors.lastname: Liu
authors.forename: Hyesoo
authors.initials: H
authors.lastname: Kim
authors.forename: Afsar
authors.initials: A
authors.lastname: Barlas
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.forename: Willie
authors.initials: W
authors.lastname: Mark
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D018360:Crystallography, X-Ray; D053595:Embryonic Stem Cells / Q000378:metabolism*; D051956:Goosecoid Protein / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D051785:Smad Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051956:Goosecoid Protein; D006657:Histones; D018398:Homeodomain Proteins; D051785:Smad Proteins; C511956:TRIM33 protein, human; D014157:Transcription Factors; C491420:Trim33 protein, mouse