MLL3/MLL4 and CBP/p300 sequentially shape dynamic enhancer landscapes in brown adipogenesis

Authors

• B Lai
• JE Lee
• L Wang
• W Peng
• K Ge

Abstract

Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes during cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors, as well as transcriptome and epigenome during brown adipogenesis. We show that MLL4 and CBP drive the dynamic enhancer epigenome, which correlates with the dynamic transcriptome. MLL3/MLL4 are required for CBP/p300 binding on enhancers activated during adipogenesis. Further, we show that MLL4 and CBP identify super-enhancers of adipogenesis and that MLL3/MLL4 control the formation of super-enhancers. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed super-enhancers of genes fully activated in brown adipose tissue such as the thermogenic Ucp1. In addition, analysis of enhancer-binding of MLL4 and CBP identifies EBF2 as a pioneer adipogenic transcription factor. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers and suggest that enhancer-priming by MLL3/MLL4 followed by enhancer-activation by CBP/p300 sequentially shape dynamic enhancer landscapes during cell differentiation. Our data also provide a rich resource for understanding epigenomic regulation of brown adipogenesis.

Scientific Focus Area: Chromosome Biology

This page was last updated on Friday, March 26, 2021