title: BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing.
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.
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Juw Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Ruitu
authors.initials: R
authors.lastname: Lv
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Jiao
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shirong
authors.initials: S
authors.lastname: Mu
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Cellular and Molecular Medicine, The Palade Laboratories, Room 231, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Zhentian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.affiliation: Epigenetics Laboratory, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Feizhen
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Hui
authors.affiliation: Department of Cellular and Molecular Medicine, The Palade Laboratories, Room 231, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Yujiang Geno
authors.initials: YG
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
authors.affiliation: 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.
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D056970:Co-Repressor Proteins; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007438:Introns / Q000235:genetics; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D010445:Peptide Elongation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D017381:Spliceosomes / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C581608:EFTUD2 protein, human; D006657:Histones; D010445:Peptide Elongation Factors; D012322:RNA Precursors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017415:Ribonucleoprotein, U5 Small Nuclear; C094763:ZMYND11 protein, human; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D008239:Lysine