Establishment of active chromatin structure at enhancer elements by mixed-lineage leukemia 1 to initiate estrogen-dependent gene expression.
Establishment of active chromatin structure at enhancer elements by mixed-lineage leukemia 1 to initiate estrogen-dependent gene expression.
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DOI：
10.1093/nar/gkt1236
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发表时间：
2014-02
影响因子：
14.9
通讯作者：
Stallcup MR
中科院分区：
文献类型：
--
作者：
Jeong KW;Andreu-Vieyra C;You JS;Jones PA;Stallcup MR
许多全基因组分析显示，雌激素受体α与其靶基因的结合和调节与FOXA 1（一种先锋因子）与MCF-7乳腺癌细胞中邻近DNA位点的结合相关。增强子元件特异性组蛋白H3 K4 me 1/2标记在染色质中的特异性FOXA 1/ERα募集位点富集，但这些增强子标记在激素处理前在染色质中建立的机制尚不清楚。在这里，我们表明，混合谱系白血病1（MLL 1）蛋白是一个关键的决定因素，保持允许的染色质结构的TFF 1增强子区域。MLL 1占据TFF 1增强子区域，并在激素刺激前甲基化H3 K4。在体外，MLL 1直接结合到TFF 1增强子的富含CpG的区域，并且其结合依赖于DNA的低甲基化。此外，MCF-7细胞中MLL 1的缺失导致染色质可及性的显著降低以及FOXA 1和ERα向增强子元件的募集。我们的研究定义了MLL 1在CpG富集区域中使组蛋白H3 K4甲基化标记成核以维持容许的染色质结构并允许FOXA 1和雌激素受体α结合到乳腺癌细胞中的转录调控位点的机制。
A number of genome-wide analyses have revealed that estrogen receptor α binding to and regulation of its target genes correlate with binding of FOXA1, a pioneer factor, to nearby DNA sites in MCF-7 breast cancer cells. The enhancer element-specific histone H3K4me1/2 mark is enriched at the specific FOXA1/ERα recruitment sites in chromatin, but the mechanism by which these enhancer marks are established in chromatin before hormone treatment is unclear. Here, we show that mixed-lineage leukemia 1 (MLL1) protein is a key determinant that maintains permissive chromatin structure of the TFF1 enhancer region. MLL1 occupies the TFF1 enhancer region and methylates H3K4 before hormone stimulation. In vitro, MLL1 binds directly to the CpG-rich region of the TFF1 enhancer, and its binding is dependent on hypomethylation of DNA. Furthermore, the depletion of MLL1 in MCF-7 cells results in a dramatic decrease of chromatin accessibility and recruitment of FOXA1 and ERα to the enhancer element. Our study defines the mechanism by which MLL1 nucleates histone H3K4 methylation marks in CpG-enriched regions to maintain permissive chromatin architecture and allow FOXA1 and estrogen receptor α binding to transcriptional regulatory sites in breast cancer cells.
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作者：
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