FOXA1 Directs H3K4 Monomethylation at Enhancers via Recruitment of the Methyltransferase MLL3.
FOXA1 Directs H3K4 Monomethylation at Enhancers via Recruitment of the Methyltransferase MLL3.
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DOI：
10.1016/j.celrep.2016.11.028
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发表时间：
2016-12-06
期刊：
影响因子：
8.8
通讯作者：
Carroll JS
中科院分区：
文献类型：
--
作者：
Jozwik KM;Chernukhin I;Serandour AA;Nagarajan S;Carroll JS
FOXA1是一种先驱因子，它与富含H3K4单甲基化和双甲基化(H3K4me1和H3K4me2)的增强子区域结合。我们对ER-α阳性的乳腺癌细胞进行了FOXA1内源性蛋白快速免疫沉淀-质谱仪(RIME)筛选，发现组蛋白赖氨酸N-甲基转移酶(MLL3)是FOXA1与内源性蛋白的最高相互作用蛋白。MLL3通常被认为在启动子区域诱导H3K4me3，但最近的研究结果表明，它可能有助于H3K4me1的沉积。我们在乳腺癌细胞中进行了MLL3染色质免疫沉淀测序(CHIP-SEQ)，发现MLL3占据了由FOXA1占有率以及H3K4me1和H3K4me2标记的区域。MLL3的结合依赖于FOXA1，表明FOXA1将MLL3招募到染色质。MLL3沉默降低了增强子元件上的H3K4me1，但对增强子元件上的H3K4me3没有明显影响。我们提出了一种机制，即先锋因子FOXA1招募染色质修饰物MLL3来促进H3K4me1组蛋白标记的沉积，随后划分活性增强子元件。染色质相关蛋白的FOXA1质谱鉴定MLL3FOXA1招募MLL3在FOXA1结合的增强剂MLL3上沉积H3K4me1 GRHL2促进ERα依赖的基因转录和增殖GRHL2在增强剂Jozwik等人上共同占据ERα、FOXA1和MLL3区域。证明FOXA1可以通过招募染色质相关的组蛋白甲基转移酶MLL3来介导增强剂上的单甲基化来激活增强剂。这将FOXA1确定为建立调控活性染色质标记的增强剂的上游调控元件。
FOXA1 is a pioneer factor that binds to enhancer regions that are enriched in H3K4 mono- and dimethylation (H3K4me1 and H3K4me2). We performed a FOXA1 rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells and found histone-lysine N-methyltransferase (MLL3) as the top FOXA1-interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition. We performed MLL3 chromatin immunoprecipitation sequencing (ChIP-seq) in breast cancer cells, and MLL3 was shown to occupy regions marked by FOXA1 occupancy and H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. MLL3 silencing decreased H3K4me1 at enhancer elements but had no appreciable impact on H3K4me3 at enhancer elements. We propose a mechanism whereby the pioneer factor FOXA1 recruits the chromatin modifier MLL3 to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements. Mass spectrometry of chromatin-associated proteins with FOXA1 identifies MLL3 FOXA1 recruits MLL3 to deposit H3K4me1 on FOXA1-bound enhancers MLL3 promotes ERα-dependent gene transcription and proliferation GRHL2 co-occupies regions of ERα, FOXA1, and MLL3 on enhancers Jozwik et al. demonstrate that FOXA1 can activate enhancers by recruiting the chromatin-associated histone methyltransferase MLL3 to mediate monomethylation on enhancers. This identifies FOXA1 as an upstream regulatory element in the establishment of enhancers that regulates active chromatin marks.
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