Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells
Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells
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DOI：
10.1101/gad.194209.112
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发表时间：
2012-08-01
影响因子：
10.5
通讯作者：
Bird, Adrian
中科院分区：
文献类型：
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作者：
Clouaire, Thomas;Webb, Shaun;Bird, Adrian
组蛋白H3Lys 4(H3K4me3)的三甲基化是启动子活性和稳定性的标志。Set1复合体与大多数体细胞H3K4me3有关，包含保守的亚基CxxC Finger Protein 1(Cfp1)，它与未甲基化的CPGS结合，并将H3K4me3与CpG岛(CGI)连接起来。在这里，我们报告Cfp1在胚胎干细胞中组织全基因组H3K4me3中扮演着意想不到的角色。Cfp1缺乏导致了两种截然不同的表型：在表达的CGI相关基因上H3K4me3的急剧丢失，对转录的影响最小，以及在许多调节区产生“异位的‘’H3K4me3峰”。Cfp1的DNA结合对于将H3K4me3靶向活性基因是必不可少的，但为了防止异位的H3K4me3峰，Cfp1是必需的。增强子的异位峰的出现通常与附近基因的表达增加相一致。这表明CpG靶向防止H3K4me3向不适当的染色质隔间“泄漏”。我们的结果表明，Cfp1是一个特异性因子，它整合了包括启动子CpG含量和基因活性在内的多种信号，来调节H3K4me3的全基因组模式。
Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised promoters. The Set1 complex is responsible for most somatic H3K4me3 and contains the conserved subunit CxxC finger protein 1 (Cfp1), which binds to unmethylated CpGs and links H3K4me3 with CpG islands (CGIs). Here we report that Cfp1 plays unanticipated roles in organizing genome-wide H3K4me3 in embryonic stem cells. Cfp1 deficiency caused two contrasting phenotypes: drastic loss of H3K4me3 at expressed CGI-associated genes, with minimal consequences for transcription, and creation of "ectopic'' H3K4me3 peaks at numerous regulatory regions. DNA binding by Cfp1 was dispensable for targeting H3K4me3 to active genes but was required to prevent ectopic H3K4me3 peaks. The presence of ectopic peaks at enhancers often coincided with increased expression of nearby genes. This suggests that CpG targeting prevents "leakage'' of H3K4me3 to inappropriate chromatin compartments. Our results demonstrate that Cfp1 is a specificity factor that integrates multiple signals, including promoter CpG content and gene activity, to regulate genome-wide patterns of H3K4me3.