Quantitative assessment of higher-order chromatin structure of the INK4/ARF locus in human senescent cells
Quantitative assessment of higher-order chromatin structure of the INK4/ARF locus in human senescent cells
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DOI：
10.1111/j.1474-9726.2012.00809.x
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发表时间：
2012-06-01
期刊：
影响因子：
7.8
通讯作者：
Nakao, Mitsuyoshi
中科院分区：
文献类型：
--
作者：
Hirosue, Akiyuki;Ishihara, Ko;Nakao, Mitsuyoshi
体细胞可以通过表达特定的因子被重置为癌基因诱导衰老（OIS）细胞或诱导多能干细胞（iPS）细胞。INK4/ARF基因座编码人类9p21染色体上的p15INK4b、ARF和p16INK4a基因，其产物被称为共同关键重编程调控因子。与生长中的成纤维细胞相比，ccctc结合因子CTCF在三个基因位点沉默的iPS细胞中显著上调，而在p15INK4b和p16INK4a基因高表达的OIS细胞中则反向下调。INK4/ARF基因座中至少有3个富集ctcf的位点，具有染色质环形成活性。这些富含CTCF的位点和p16INK4a启动子在生长中的成纤维细胞中形成紧密的染色质环，而CTCF的缺失破坏了环结构。有趣的是，在OIS细胞中发现了松散的染色质结构。此外，INK4/ARF位点在iPS细胞中具有一种中间类型的染色质压实。这些结果表明，衰老细胞在INK4/ARF位点具有明显的高阶染色质特征。
Somatic cells can be reset to oncogene-induced senescent (OIS) cells or induced pluripotent stem (iPS) cells by expressing specified factors. The INK4/ARF locus encodes p15INK4b, ARF, and p16INK4a genes in human chromosome 9p21, the products of which are known as common key reprogramming regulators. Compared with growing fibroblasts, the CCCTC-binding factor CTCF is remarkably up-regulated in iPS cells with silencing of the three genes in the locus and is reversely down-regulated in OIS cells with high expression of p15INK4b and p16INK4a genes. There are at least three CTCF-enriched sites in the INK4/ARF locus, which possess chromatin loop-forming activities. These CTCF-enriched sites and the p16INK4a promoter associate to form compact chromatin loops in growing fibroblasts, while CTCF depletion disrupts the loop structure. Interestingly, the loose chromatin structure is found in OIS cells. In addition, the INK4/ARF locus has an intermediate type of chromatin compaction in iPS cells. These results suggest that senescent cells have distinct higher-order chromatin signature in the INK4/ARF locus.