Histone Crosstalk Connects Protein Phosphatase 1{alpha} (PP1{alpha}) and Histone Deacetylase (HDAC) Pathways to Regulate the Functional Transition of Bromodomain-containing 4 (Brd4) for Inducible Gene Expression [DNA and Chromosomes]

June 17th, 2014 by Hu, X., Lu, X., Liu, R., Ai, N., Cao, Z., Li, Y., Liu, J., Yu, B., Liu, K., Wang, H., Zhou, C., Wang, Y., Han, A., Ding, F., Chen, R.

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 which 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 signal pathways and the molecular mechanism for regulating this transition process, however, are largely unknown. Here, we report a novel role of phosphorylated-Ser10 of histone H3 (H3S10ph) in governing Brd4's functional transition. We identified that the acetylated-lysine 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) signal 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 crosstalk 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.
  • Posted in Journal of Biological Chemistry, Publications
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