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Mol Cell. 2014 Oct 23;56(2):298-310. doi: 10.1016/j.molcel.2014.08.022. Epub 2014 Sep 25.

BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing.

Author information

1
Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
2
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CHS 33-228, 650 Charles E. Young Drive South, Los Angeles, CA 90095-7278, USA.
3
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
4
Department of Molecular Carcinogenesis and Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
5
Department of Cellular and Molecular Medicine, The Palade Laboratories, Room 231, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
6
Endocrinology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Epigenetics Laboratory, Institutes of Biomedical Sciences and School of Basic Medicine, Shanghai Medical College of Fudan University, Shanghai 200032, China.
7
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CHS 33-228, 650 Charles E. Young Drive South, Los Angeles, CA 90095-7278, USA. Electronic address: yxing@ucla.edu.
8
Epigenetics Laboratory, Institutes of Biomedical Sciences and School of Basic Medicine, Shanghai Medical College of Fudan University, Shanghai 200032, China. Electronic address: fei_lan@fudan.edu.cn.
9
Epigenetics Laboratory, Institutes of Biomedical Sciences and School of Basic Medicine, Shanghai Medical College of Fudan University, Shanghai 200032, China; Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: yshi@hms.harvard.edu.

Abstract

BS69 (also called ZMYND11) contains tandemly arranged PHD, BROMO, and PWWP domains, which are chromatin recognition modalities. Here, we show that BS69 selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3) via its chromatin-binding domains. We further identify BS69 association with RNA splicing regulators, including the U5 snRNP components of the spliceosome, such as EFTUD2. Remarkably, RNA sequencing shows that BS69 mainly regulates intron retention (IR), which is the least understood RNA alternative splicing event in mammalian cells. Biochemical and genetic experiments demonstrate that BS69 promotes IR by antagonizing EFTUD2 through physical interactions. We further show that regulation of IR by BS69 also depends on its binding to H3K36me3-decorated chromatin. Taken together, our study identifies an H3.3K36me3-specific reader and a regulator of IR and reveals that BS69 connects histone H3.3K36me3 to regulated RNA splicing, providing significant, important insights into chromatin regulation of pre-mRNA processing.

PMID:
25263594
PMCID:
PMC4363072
DOI:
10.1016/j.molcel.2014.08.022
[Indexed for MEDLINE]
Free PMC Article

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