MBD3 localizes at promoters, gene bodies and enhancers of active genes.
MBD3 localizes at promoters, gene bodies and enhancers of active genes.
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DOI：
10.1371/journal.pgen.1004028
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Wade PA
中科院分区：
文献类型：
--
作者：
Shimbo T;Du Y;Grimm SA;Dhasarathy A;Mav D;Shah RR;Shi H;Wade PA
Mi-2/核小体重构和组蛋白脱乙酰酶（NuRD）复合物是一种多蛋白机器，被提出通过核小体重构和组蛋白脱乙酰化活性来调节染色质结构。最近的报告描述本地化的NuRD提供了新的见解，质疑以前的模型NuRD行动，但不完全一致。在这里，我们使用两种独立的基因组技术：DNA腺嘌呤甲基转移酶鉴定（DamID）和ChIP-seq，在两种人乳腺癌细胞系（MCF-7和MDA-MB-231）中提供了内源性MBD 3（NuRD复合物的一种组分）的位置分析。我们观察到所得到的基因组定位的一致性，这表明这些研究正在收敛于癌细胞基因组中NuRD的稳健图谱。MBD 3优先与由H3 K4 me 3标记的富含CpG的启动子相关联，并显示跨基因体的细胞类型特异性定位，在转录起始位点周围达到峰值。由MBD 3结合的位点的子集在H3 K27 ac中富集，并且在三维空间中与启动子物理接近，表明作为增强子的功能。在经H3 K27 me 3修饰的启动子处也注意到MBD 3富集。染色质的功能分析表明，MBD 3调节启动子附近和基因体中的核小体占有率。这些数据表明，MBD 3，并通过扩展的NuRD复合物，可能有多种作用，在微调表达的活性和沉默的基因，代表了一个重要的步骤，在定义调控机制，NuRD复合物控制染色质结构和修饰状态。染色质结构受到多种机制的严格调节;其失调与发育异常和疾病有关。提出Mi-2/核小体重塑和组蛋白脱乙酰酶（NuRD）复合物通过改变染色质的基本构建块（核小体）的位置和/或化学性质来调节染色质结构。遗传学已经证明NuRD对正常发育很重要，但NuRD如何调节染色质结构的详细机制仍不清楚。在这里，我们研究的定位和功能MBD 3，NURD的一个组成部分，在两个人乳腺癌细胞系使用两个独立的基因组技术。我们的数据表明，现有的模型，与NuRD转录抑制，是不完全正确的。相反，MBD 3在活性基因处显示细胞类型特异性定位。此外，我们发现了一个以前未确定的MBD 3跨基因体的定位，并确定了MBD 3在核小体组织中的调节作用。我们的数据为解决NuRD控制染色质结构和核生物学的机制提供了一个可靠的起点。
The Mi-2/nucleosome remodeling and histone deacetylase (NuRD) complex is a multiprotein machine proposed to regulate chromatin structure by nucleosome remodeling and histone deacetylation activities. Recent reports describing localization of NuRD provide new insights that question previous models on NuRD action, but are not in complete agreement. Here, we provide location analysis of endogenous MBD3, a component of NuRD complex, in two human breast cancer cell lines (MCF-7 and MDA-MB-231) using two independent genomic techniques: DNA adenine methyltransferase identification (DamID) and ChIP-seq. We observed concordance of the resulting genomic localization, suggesting that these studies are converging on a robust map for NuRD in the cancer cell genome. MBD3 preferentially associated with CpG rich promoters marked by H3K4me3 and showed cell-type specific localization across gene bodies, peaking around the transcription start site. A subset of sites bound by MBD3 was enriched in H3K27ac and was in physical proximity to promoters in three-dimensional space, suggesting function as enhancers. MBD3 enrichment was also noted at promoters modified by H3K27me3. Functional analysis of chromatin indicated that MBD3 regulates nucleosome occupancy near promoters and in gene bodies. These data suggest that MBD3, and by extension the NuRD complex, may have multiple roles in fine tuning expression for both active and silent genes, representing an important step in defining regulatory mechanisms by which NuRD complex controls chromatin structure and modification status. Chromatin structure is tightly regulated by multiple mechanisms; its dysregulation is associated with developmental abnormalities and disease. The Mi-2/nucleosome remodeling and histone deacetylase (NuRD) complex is proposed to regulate chromatin structure by changing the location and/or the chemical properties of the fundamental building block of chromatin, the nucleosome. NuRD has been shown by genetics to be important for normal development, yet the detailed mechanism of how NuRD regulates chromatin structure is still unclear. Here, we study the localization and function of MBD3, a component of NuRD, in two human breast cancer cell lines using two independent genomic technologies. Our data demonstrate that existing models, which associate NuRD with transcriptional repression, are not completely correct. Rather, MBD3 showed cell-type specific localization at active genes. Moreover, we found a previously unidentified localization of MBD3 across gene bodies and identified a regulatory role for MBD3 in nucleosome organization. Our data provide a reliable starting point from which to address mechanisms by which NuRD controls chromatin structure and nuclear biology.
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