Positive Regulation of Transcription by Human ZMYND8 through Its Association with P-TEFb Complex

• Published in: Cell reports (Cambridge) 2018-08, Vol.24 (8), p.2141-2154.e6
• Main Authors: Ghosh, Koushik, Tang, Ming, Kumari, Nidhi, Nandy, Arijit, Basu, Subham, Mall, Dheerendra Pratap, Rai, Kunal, Biswas, Debabrata
• Format: Article
• Language: English
• Subjects: histone; Humans; NuRD; P-TEFb; Positive Transcriptional Elongation Factor B - metabolism; transcription; Transcription, Genetic - genetics; Transfection; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; ZMYND8
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.07.064

Although human ZMYND8 has been implicated as a transcriptional co-repressor of multiple targets, global association of ZMYND8 with active genes and enhancer regions predicts otherwise. Here, we report an additional function of ZMYND8 in transcriptional activation through its association with the P-TEFb complex. Biochemical reconstitution analyses show that human ZMYND8, through direct association with CylcinT1, forms a minimal ZMYND8-P-TEFb complex. The importance of ZMYND8 in target gene activation, through P-TEFb complex recruitment, is demonstrated on chromosomally integrated reporter gene as well as native target genes in vivo. Physiologically, we further show that the ZMYND8-P-TEFb complex-mediated transcriptional activation is required for all-trans retinoic acid (ATRA)-mediated differentiation of neuronal precursor cells. Finally, to detail the dual activator and repressor nature, mechanistically we show that, through its putative coiled-coil domain, ZMYND8 forms a homodimer that preferentially associates with the activator P-TEFb complex, whereas the monomer associates with the CHD4 subunit of repressor NuRD complex. [Display omitted] •ZMYND8-mediated P-TEFb complex recruitment activates transcription•Differentiation of SH-SH5Y cells requires transcriptional activation by ZMYND8•ZMYND8 exists as monomer as well as dimer•Preferential association of CHD4 with monomer and P-TEFb with dimer form of ZMYND8 Ghosh et al. report that coiled-coil domain-dependent dimerization of ZMYND8 positively regulates transcription through P-TEFb complex recruitment, whereas monomeric ZMYND8 associates with NuRD complex for transcriptional repression. ZMYND8-mediated P-TEFb complex recruitment is required for target gene activation during retinoic acid-induced differentiation of SH-SY5Y cells.