Transcriptional activation by pRB and its coordination with SWI/SNF recruitment.
Transcriptional activation by pRB and its coordination with SWI/SNF recruitment.
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DOI：
10.1158/0008-5472.can-10-2205
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Moran E
中科院分区：
文献类型：
--
作者：
Flowers S;Beck GR Jr;Moran E
癌症生物学的一个核心问题是为什么大多数肿瘤易感基因仅与有限类型的癌症相关。视网膜母细胞瘤易感基因 Rb1 的人类种系突变仅与视网膜母细胞瘤和骨肉瘤密切相关，尽管该基因普遍表达。 pRB 及其近亲 p107 和 p130 的功能分析主要集中在它们在抑制所有组织类型增殖中的作用，但遗传证据表明成骨细胞分化对 pRB 的积极需求，这与骨肉瘤易感性更直接相关。尽管如此，pRB 的潜在启动子靶点及其在正常分化成骨细胞中的作用仍然没有得到充分的表征。在此，成骨细胞分化的早期标志物碱性磷酸酶被确定为 pRB 的直接启动子激活靶标。 pRB 在该启动子上的作用之一是取代组蛋白赖氨酸去甲基化酶 KDM5A，从而有利于启动子激活标记 H3K4 的三甲基化。该启动子分析揭示了 pRB 介导的转录激活的一个主要新方面是其在招募激活的 SWI/SNF 染色质重塑复合物中的作用。 SWI/SNF 是组织特异性基因表达的关键协调者。在成骨细胞中，含有 BRM ATP 酶的 SWI/SNF 复合物会抑制成骨细胞特异性基因以维持前体状态，而替代的 ATP 酶 BRG1 则可区分 RNA 聚合酶 II 招募所需的激活 SWI/SNF 复合物。碱性磷酸酶启动子上从 BRM 到 BRG1 的转换标志着分化的开始，并以精确的两步机制完成。含有 BRM 的 SWI/SNF 的解离取决于 p300，含有 BRG1 的 SWI/SNF 的结合取决于 pRB。
A central question in cancer biology is why most tumor susceptibility genes are linked with only limited types of cancer. Human germ-line mutation of the retinoblastoma susceptibility gene Rb1 is closely linked with just retinoblastoma and osteosarcoma, although the gene is universally expressed. Functional analysis of pRB and its close relatives, p107 and p130, has largely focused on their roles in repression of proliferation across all tissue types, but genetic evidence indicates an active requirement for pRB in osteoblast differentiation that correlates more directly with osteosarcoma susceptibility. Still, potential promoter targets of pRB and its role in normally differentiating osteoblasts remain insufficiently characterized. Here, an early marker of osteoblast differentiation, alkaline phosphatase, is identified as a direct promoter activation target of pRB. One role of pRB on this promoter is to displace the histone lysine demethylase KDM5A, thereby favoring trimethylation of H3K4, a promoter activation mark. A major new aspect of pRB-mediated transcriptional activation revealed in this promoter analysis is its role in recruitment of an activating SWI/SNF chromatin-remodeling complex. SWI/SNF is a critical coordinator of tissue-specific gene expression. In osteoblasts, SWI/SNF complexes containing the BRM ATPase repress osteoblast-specific genes to maintain the precursor state, while the alternative ATPase, BRG1, distinguishes an activating SWI/SNF complex necessary for RNA polymerase-II recruitment. A switch from BRM to BRG1 on the alkaline phosphatase promoter marks the onset of differentiation and is accomplished in a precise two-step mechanism. Dissociation of BRM-containing SWI/SNF depends on p300, and association of BRG1-containing SWI/SNF depends on pRB.