Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain.
Recognition of histone covalent modifications by chromatin-binding protein modules ("readers") constitutes a major mechanism for epigenetic regulation, typified by bromodomains that bind acetyllysine. Non-acetyl histone lysine acylations (e.g., crotonylation, butyrylation, propionylation) have been recently identified, but readers that prefer these acylations have not been characterized. Here we report that the AF9 YEATS domain displays selectively higher binding affinity for crotonyllysine over acetyllysine. Structural studies revealed an extended aromatic sandwiching cage with crotonyl specificity arising from π-aromatic and hydrophobic interactions between crotonyl and aromatic rings. These features are conserved among the YEATS, but not the bromodomains. Using a cell-based model, we showed that AF9 co-localizes with crotonylated histone H3 and positively regulates gene expression in a YEATS domain-dependent manner. Our studies define the evolutionarily conserved YEATS domain as a family of crotonyllysine readers and specifically demonstrate that the YEATS domain of AF9 directly links histone crotonylation to active transcription.
MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Beijing 100084, PRC; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, PRC.
Yuanyuan
Y
Li
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Benjamin R
BR
Sabari
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Tatyana
T
Panchenko
Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hong
H
Wen
MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Beijing 100084, PRC; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, PRC.
Dan
D
Zhao
MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Beijing 100084, PRC; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, PRC.
Haipeng
H
Guan
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Liling
L
Wan
Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
He
H
Huang
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
Zhanyun
Z
Tang
Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Yingming
Y
Zhao
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
Robert G
RG
Roeder
Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Xiaobing
X
Shi
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: alliscd@mail.rockefeller.edu.
C David
CD
Allis
MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Beijing 100084, PRC; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, PRC; Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PRC. Electronic address: lht@tsinghua.edu.cn.
Haitao
H
Li
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D042002:Chromatin Assembly and Disassembly; D003437:Crotonates / Q000378:metabolism*; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D000067996:RAW 264.7 Cells; D016601:RNA-Binding Proteins / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000092468:Bromodomain Containing Proteins
D003437:Crotonates; D006657:Histones; D008239:Lysine; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C109106:BRD3 protein, human; D000092468:Bromodomain Containing Proteins; C518476:Brd3 protein, mouse; C489901:MLLT3 protein, human; C489902:Mllt3 protein, mouse