SETDB1 modulates PRC2 activity at developmental genes independently of H3K9 trimethylation in mouse ES cells
- Qi Fei1,5,
- Xiaoqin Yang2,5,
- Hua Jiang1,
- Qian Wang2,
- Yanyan Yu1,
- Yiling Yu1,
- Wei Yi1,
- Shaolian Zhou1,
- Taiping Chen3,6,
- Chris Lu1,
- Peter Atadja1,
- Xiaole Shirley Liu4,
- En Li1,
- Yong Zhang2 and
- Jianyong Shou1,7
- 1China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
- 2Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China;
- 3Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA;
- 4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts 02115, USA
- Corresponding authors: shou_jian_yong{at}lilly.com, yzhang{at}tongji.edu.cn
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↵5 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.177576.114.
- Received April 24, 2014.
- Accepted July 8, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
