Journal
CELL REPORTS
Volume 24, Issue 8, Pages 2141-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.07.064
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Funding
- Ramalingaswami Re-entry Fellowship
- Wellcome Trust DBT Intermediate Fellowship [IA/I/14/1/501287]
- CSIR-Senior Research Fellowship
- UGC Senior Research Fellowship
- DBT Fellowship
- CSIR-IICB
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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 ZMYND8P-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.
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