PT  - JOURNAL ARTICLE
AU  - Younghoon Jang
AU  - Chaochen Wang
AU  - Aaron Broun
AU  - Young-Kwon Park
AU  - Lenan Zhuang
AU  - Ji-Eun Lee
AU  - Eugene Froimchuk
AU  - Chengyu Liu
AU  - Kai Ge
TI  - H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development
AID  - 10.1101/301986
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 301986
4099  - http://biorxiv.org/content/early/2018/04/16/301986.short
4100  - http://biorxiv.org/content/early/2018/04/16/301986.full
AB  - Histone H3K4 mono-methyltransferases MLL3 and MLL4 (MLL3/4) are required for enhancer activation during cell differentiation, though the mechanism is incompletely understood. To address MLL3/4 enzymatic activity in enhancer regulation, we have generated two mouse lines: one expressing H3.3K4M, a lysine-4-to-methionine (K4M) mutation of histone H3.3 that inhibits H3K4 methylation, and the other carrying conditional double knockout of MLL3/4 enzymatic SET domains. Expression of H3.3K4M in lineage-specific precursor cells depletes H3K4 methylation and prevents adipogenesis and adipose tissue development. Mechanistically, H3.3K4M prevents enhancer activation in adipogenesis by destabilizing MLL3/4 proteins but not other Set1-like H3K4 methyltransferases. Notably, deletion of the enzymatic SET domain of MLL3/4 in lineage-specific precursor cells mimics H3.3K4M expression and prevents adipose tissue development. Interestingly, destabilization of MLL3/4 by H3.3K4M in adipocytes does not affect adipose tissue maintenance and function. Together, our findings indicate that H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development.