title: SETDB1 modulates PRC2 activity at developmental genes independently of H3K9 trimethylation in mouse ES cells.
abstract: SETDB1, a histone methyltransferase responsible for methylation of histone H3 lysine 9 (H3K9), is involved in maintenance of embryonic stem (ES) cells and early embryonic development of the mouse. However, how SETDB1 regulates gene expression during development is largely unknown. Here, we characterized genome-wide SETDB1 binding and H3K9 trimethylation (H3K9me3) profiles in mouse ES cells and uncovered two distinct classes of SETDB1 binding sites, termed solo and ensemble peaks. The solo peaks were devoid of H3K9me3 and enriched near developmental regulators while the ensemble peaks were associated with H3K9me3. A subset of the SETDB1 solo peaks, particularly those near neural development-related genes, was found to be associated with Polycomb Repressive Complex 2 (PRC2) as well as PRC2-interacting proteins JARID2 and MTF2. Genetic deletion of Setdb1 reduced EZH2 binding as well as histone 3 lysine 27 (H3K27) trimethylation level at SETDB1 solo peaks and facilitated neural differentiation. Furthermore, we found that H3K27me3 inhibits SETDB1 methyltransferase activity. The currently identified reciprocal action between SETDB1 and PRC2 reveals a novel mechanism underlying ES cell pluripotency and differentiation regulation.
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Qi
authors.initials: Q
authors.lastname: Fei
authors.affiliation: Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China;
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Yang
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Yiling
authors.initials: Y
authors.lastname: Yu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Shaolian
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA;
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Chris
authors.initials: C
authors.lastname: Lu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Xiaole Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China;
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
authors.forename: Jianyong
authors.initials: J
authors.lastname: Shou
mesh_terms: D000818:Animals; D001665:Binding Sites; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C516239:SETDB1 protein, mouse