FOXA1 mediates p16INK4a activation during cellular senescence
FOXA1 mediates p16INK4a activation during cellular senescence
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FOXA1 在细胞衰老过程中介导 p16INK4a 激活
DOI：
10.1038/emboj.2013.35
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发表时间：
2013-03-20
期刊：
影响因子：
11.4
通讯作者：
Tong, Tanjun
中科院分区：
文献类型：
--
作者：
Li, Qian;Zhang, Yu;Tong, Tanjun
p16（INK 4a）是细胞衰老的主要调控因子之一，其转录调控机制已被广泛研究。然而，很少有人知道染色质动力学发生在其启动子和远端增强子。在这里，我们报告说，叉头框A1蛋白（FOXA 1）是显着上调复制和癌基因诱导的衰老，并反过来激活转录p16（INK 4a）通过多种机制。除了作为经典的序列特异性转录激活因子，FOXA 1结合导致衰老成纤维细胞中p16（INK 4a）启动子处的核小体密度降低。此外，FOXA 1本身是Polycomb介导的抑制的直接靶点，拮抗Polycomb在p16（INK 4a）位点的功能。最后，在p16（INK 4a）基因组区域的推定FOXA 1结合位点的系统调查揭示了一个类似的150 kb的远端元件，可以环回启动子和p16（INK 4a）的表达增强。总的来说，我们的研究结果建立了FOXA 1控制细胞衰老过程中p16（INK 4a）表达的几种机制。The EMBO Journal（2013）32，858-873. doi：10.1038/daj.2013.35; 2013年2月26日在线发布
Mechanisms governing the transcription of p16(INK4a), one of the master regulators of cellular senescence, have been extensively studied. However, little is known about chromatin dynamics taking place at its promoter and distal enhancer. Here, we report that Forkhead box A1 protein (FOXA1) is significantly upregulated in both replicative and oncogene-induced senescence, and in turn activates transcription of p16(INK4a) through multiple mechanisms. In addition to acting as a classic sequence-specific transcriptional activator, FOXA1 binding leads to a decrease in nucleosome density at the p16(INK4a) promoter in senescent fibroblasts. Moreover, FOXA1, itself a direct target of Polycomb-mediated repression, antagonizes Polycomb function at the p16(INK4a) locus. Finally, a systematic survey of putative FOXA1 binding sites in the p16(INK4a) genomic region revealed an similar to 150 kb distal element that could loop back to the promoter and potentiate p16(INK4a) expression. Overall, our findings establish several mechanisms by which FOXA1 controls p16(INK4a) expression during cellular senescence. The EMBO Journal (2013) 32, 858-873. doi:10.1038/emboj.2013.35; Published online 26 February 2013