Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster
Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster
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DOI：
10.1038/emboj.2009.81
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发表时间：
2009-05-06
期刊：
影响因子：
11.4
通讯作者：
Nakao, Mitsuyoshi
中科院分区：
文献类型：
--
作者：
Mishiro, Tsuyoshi;Ishihara, Ko;Nakao, Mitsuyoshi
长程调控元件和染色质高级结构协调多个基因簇的表达，CTCF/cohesin介导的染色质绝缘子可能是这种调控的关键。人载脂蛋白（APO）A1/C3/A4/A5基因区，其改变增加血脂异常和动脉粥样硬化的风险，至少被三个CTCF富集位点和三个粘着蛋白RAD 21富集位点（两个与CTCF位点重叠）分隔，导致通过绝缘子之间的相互作用形成两个转录的染色质环。C3增强子和APOC 3/A4/A5启动子位于同一环中，其中APOC 3/A4启动子指向C3增强子，而APOA 1启动子存在于不同环中。CTCF或RAD 21的缺失破坏染色质环结构，以及APO表达和转录因子肝细胞核因子（HNF）-4 α和RNA聚合酶II转录活性形式在APO启动子处的定位的显著变化。因此，CTCF/cohesin介导的绝缘子维持染色质环的形成和转录装置在启动子处的定位，这表明染色质绝缘在控制成簇基因的表达中起重要作用。The EMBO Journal（2009）28，1234-1245. doi：10.1038/200j。2009.81; 2009年3月26日在线发布
Long-range regulatory elements and higher-order chromatin structure coordinate the expression of multiple genes in cluster, and CTCF/cohesin-mediated chromatin insulator may be a key in this regulation. The human apolipoprotein (APO) A1/C3/A4/A5 gene region, whose alterations increase the risk of dyslipidemia and atherosclerosis, is partitioned at least by three CTCF-enriched sites and three cohesin protein RAD21-enriched sites (two overlap with the CTCF sites), resulting in the formation of two transcribed chromatin loops by interactions between insulators. The C3 enhancer and APOC3/A4/A5 promoters reside in the same loop, where the APOC3/A4 promoters are pointed towards the C3 enhancer, whereas the APOA1 promoter is present in the different loop. The depletion of either CTCF or RAD21 disrupts the chromatin loop structure, together with significant changes in the APO expression and the localization of transcription factor hepatocyte nuclear factor (HNF)-4 alpha and transcriptionally active form of RNA polymerase II at the APO promoters. Thus, CTCF/cohesin-mediated insulators maintain the chromatin loop formation and the localization of transcriptional apparatus at the promoters, suggesting an essential role of chromatin insulation in controlling the expression of clustered genes. The EMBO Journal (2009) 28, 1234-1245. doi: 10.1038/emboj. 2009.81; Published online 26 March 2009