Methylation specifies distinct estrogen-induced binding site repertoires of CBP to chromatin
Methylation specifies distinct estrogen-induced binding site repertoires of CBP to chromatin
复制标题
DOI：
10.1101/gad.619211
复制
发表时间：
2011-06-01
影响因子：
10.5
通讯作者：
Gronemeyer, Hinrich
中科院分区：
文献类型：
--
作者：
Ceschin, Danilo Guillermo;Walia, Mannu;Gronemeyer, Hinrich
多种信号通路最终通过募集表观遗传酶来调节嵌入基因启动子染色质中的表观遗传信息。我们发现，在雌激素调节的基因编程中，乙酰转移酶CREB结合蛋白（CBP）在体内被辅激活子相关的精氨酸甲基转移酶（CARM 1）特异性地甲基化。CARM 1依赖性CBP甲基化和p160共激活因子是雌激素诱导的染色质靶向募集所必需的。值得注意的是，甲基化增加CBP的组蛋白乙酰转移酶（HAT）活性，并刺激其自动乙酰化。比较全基因组染色质免疫沉淀测序（ChIP-seq）研究揭示了雌激素将p160、CBP和甲基CBP（meCBP）募集（或不募集）到染色质靶点的各种模式。此外，（1）p160 RAC 3蛋白，（2）总CBP中给定meCBP种类的分数，和（3）不同meCBP种类的相对募集中的显著靶基因特异性变化表明存在共调节因子募集的靶基因特异性“指纹”。交叉ChIP-seq和转录组学图谱揭示了雌激素调节基因网络中存在meCBP“枢纽”。总之，我们的数据为一种前所未有的机制提供了证据，通过这种机制，CARM 1依赖性CBP甲基化导致雌激素招募的meCBP物种与不同的HAT活性发生基因选择性关联，并指定不同的靶基因枢纽，从而使雌激素受体编程多样化。
Multiple signaling pathways ultimately modulate the epigenetic information embedded in the chromatin of gene promoters by recruiting epigenetic enzymes. We found that, in estrogen-regulated gene programming, the acetyltransferase CREB-binding protein (CBP) is specifically and exclusively methylated by the coactivator-associated arginine methyltransferase (CARM1) in vivo. CARM1-dependent CBP methylation and p160 coactivators were required for estrogen-induced recruitment to chromatin targets. Notably, methylation increased the histone acetyltransferase (HAT) activity of CBP and stimulated its autoacetylation. Comparative genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) studies revealed a variety of patterns by which p160, CBP, and methyl-CBP (meCBP) are recruited (or not) by estrogen to chromatin targets. Moreover, significant target gene-specific variation in the recruitment of (1) the p160 RAC3 protein, (2) the fraction of a given meCBP species within the total CBP, and (3) the relative recruitment of different meCBP species suggests the existence of a target gene-specific "fingerprint" for coregulator recruitment. Crossing ChIP-seq and transcriptomics profiles revealed the existence of meCBP "hubs" within the network of estrogen-regulated genes. Together, our data provide evidence for an unprecedented mechanism by which CARM1-dependent CBP methylation results in gene-selective association of estrogen-recruited meCBP species with different HAT activities and specifies distinct target gene hubs, thus diversifying estrogen receptor programming.