title: Histone cross-talk connects protein phosphatase 1α (PP1α) and histone deacetylase (HDAC) pathways to regulate the functional transition of bromodomain-containing 4 (BRD4) for inducible gene expression.
abstract: Transcription elongation has been recognized as a rate-limiting step for the expression of signal-inducible genes. Through recruitment of positive transcription elongation factor P-TEFb, the bromodomain-containing protein BRD4 plays critical roles in regulating the transcription elongation of a vast array of inducible genes that are important for multiple cellular processes. The diverse biological roles of BRD4 have been proposed to rely on its functional transition between chromatin targeting and transcription regulation. The signaling pathways and the molecular mechanism for regulating this transition process, however, are largely unknown. Here, we report a novel role of phosphorylated Ser(10) of histone H3 (H3S10ph) in governing the functional transition of BRD4. We identified that the acetylated lysines 5 and 8 of nucleosomal histone H4 (H4K5ac/K8ac) is the BRD4 binding site, and the protein phosphatase PP1α and class I histone deacetylase (HDAC1/2/3) signaling pathways are essential for the stress-induced BRD4 release from chromatin. In the unstressed state, phosphorylated H3S10 prevents the deacetylation of nucleosomal H4K5ac/K8ac by HDAC1/2/3, thereby locking up the majority of BRD4 onto chromatin. Upon stress, PP1α-mediated dephosphorylation of H3S10ph allows the deacetylation of nucleosomal H4K5ac/K8ac by HDAC1/2/3, thereby leading to the release of chromatin-bound BRD4 for subsequent recruitment of P-TEFb to enhance the expression of inducible genes. Therefore, our study revealed a novel mechanism that the histone cross-talk between H3S10ph and H4K5ac/K8ac connects PP1α and HDACs to govern the functional transition of BRD4. Combined with previous studies on the regulation of P-TEFb activation, the intricate signaling network for the tight control of transcription elongation is established.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Runzhong
authors.initials: R
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Nanping
authors.initials: N
authors.lastname: Ai
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Jiangfang
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China.
authors.forename: Aidong
authors.initials: A
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China. Electronic address: fding7@gmail.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China. Electronic address: chenrc@xmu.edu.cn.
authors.forename: Ruichuan
authors.initials: R
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D006655:Histone Deacetylases; D006657:Histones; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D054645:Protein Phosphatase 1; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BRD4; Histone Acetylation; Histone Deacetylase (HDAC); Histone Phosphorylation; Inducible Gene Expression; P-TEFb; Phosphoprotein Phosphatase 1 (PP1); Stress Response; Transcription Elongation Factor; histone Modification