Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation.
Solving the biological roles of covalent histone modifications, including monoubiquitination of histone H2A, and the molecular mechanisms by which these modifications regulate specific transcriptional programs remains a central question for all eukaryotes. Here we report that the N-CoR/HDAC1/3 complex specifically recruits a specific histone H2A ubiquitin ligase, 2A-HUB/hRUL138, to a subset of regulated gene promoters. 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. We suggest that distinct H2A ubiquitinases, each recruited based on interactions with different corepressor complexes, contribute to distinct transcriptional repression programs.
Zhou
Wenlai
W
Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Zhu
Ping
P
Wang
Jianxun
J
Pascual
Gabriel
G
Ohgi
Kenneth A
KA
Lozach
Jean
J
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D010441:Peptide Chain Elongation, Translational / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D054829:RING Finger Domains; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics*; D035602:Transcriptional Elongation Factors / Q000037:antagonists & inhibitors; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000235:genetics; D000099186:Histone Deacetylase 3
D018925:Chemokines; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D006657:Histones; D008025:Ligases; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D012319:RNA Polymerase II; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D035602:Transcriptional Elongation Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099186:Histone Deacetylase 3; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse; C073537:SSRP1 protein, human; C476989:DZIP3 protein, human; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse