MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis.
MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis.
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DOI：
10.1093/nar/gkx234
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发表时间：
2017-06-20
影响因子：
14.9
通讯作者：
Ge K
中科院分区：
文献类型：
--
作者：
Lai B;Lee JE;Jang Y;Wang L;Peng W;Ge K
组蛋白H3K4me1/2甲基转移酶ML3/MLL4和H3K27乙酰基转移酶CBP/p300是主要的增强子表观基因组编写者。为了了解这些表观基因组编写者如何在细胞分化中协调增强子环境，我们描述了MLL4，CBP，谱系决定转录因子(EBF2，C/EBPβ，C/EBPα，PPARγ)，共激活因子MED1，RNA聚合酶II，以及表观基因组(H3K4me1/2/3，H3K9me2，H3K27me3，H3K36me3，H3K27ac)，转录体和染色质开放的基因组结合。我们发现MLL4和CBP驱动与动态转录组相关的动态增强子表观基因组。MLL3/MLL4是CBP/p300与脂肪形成过程中激活的增强剂结合所必需的。此外，MLL4和CBP识别脂肪生成的超级增强剂(SE)，并且ML3/MLL4是SE形成所必需的。最后，在培养分化的棕色脂肪细胞中，MLL4确定了蝙蝠中完全激活的基因的启动序列，如Ucp1。比较棕色和白色脂肪形成中MLL4定义的SE，确定了可能参与蝙蝠功能的棕色特定SE相关基因。这些结果确立了MLL3/MLL4和CBP/p300是主要的增强子表观编写者，并表明在细胞分化过程中，由MLL3/MLL4启动增强子，然后由CBP/p300激活增强子，从而形成动态的增强子景观。我们的数据也为理解棕色脂肪形成的表观基因组调控提供了丰富的资源。
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 in cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors (EBF2, C/EBPβ, C/EBPα, PPARγ), coactivator MED1, RNA polymerase II, as well as epigenome (H3K4me1/2/3, H3K9me2, H3K27me3, H3K36me3, H3K27ac), transcriptome and chromatin opening during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT). 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, MLL4 and CBP identify super-enhancers (SEs) of adipogenesis and that MLL3/MLL4 are required for SE formation. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed SEs of genes fully activated in BAT such as Ucp1. Comparison of MLL4-defined SEs in brown and white adipogenesis identifies brown-specific SE-associated genes that could be involved in BAT functions. 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.