Role of chromatin and transcriptional co-regulators in mediating p63-genome interactions in keratinocytes.
Role of chromatin and transcriptional co-regulators in mediating p63-genome interactions in keratinocytes.
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DOI：
10.1186/1471-2164-15-1042
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发表时间：
2014-11-29
期刊：
影响因子：
4.4
通讯作者：
Buck MJ
中科院分区：
文献类型：
--
作者：
Sethi I;Sinha S;Buck MJ
转录因子（TF）p63是表皮发育和分化的主要调节因子，如从p63敲除小鼠的显著皮肤表型所证明的。此外，p63单独的异位表达足以在体内将单层上皮转化为复层上皮组织，并且p63是成纤维细胞有效转分化为角质形成细胞所需的。然而，人们对p63功能的分子机制知之甚少，特别是它如何在基因组中选择靶位点。p63作为转录的激活因子和抑制因子，识别在人类基因组中出现超过100万次的典型结合基序。但是，在人类角质形成细胞中，少于12，000个这些位点在体内结合，这表明潜在的染色质结构和协作TF介导p63-基因组相互作用。我们发现，染色质结构在p63结合的目标具有独特的功能，并可用于分类p63目标近端启动子（1%），增强子（59%）和抑制或无活性（40%）的调控元件。我们的分析表明，染色质修饰H3 K4 me 1，H3 K27 me 3，沿着与整体染色质可及性状态可以准确地预测真正的p63结合位点，而无需先验DNA序列信息。然而，有趣的是，p63结合基序与可及性和H3 K4 me 1水平之间存在定性相关性。此外，我们使用了一种全面的计算机模拟方法，该方法利用ENCODE数据来识别几种已知的TF，如AP 1，AP 2和新型TF（例如RFX 5）。它可以与p63合作调节其在角质形成细胞中的多种生物学功能。我们的分析表明，角质形成细胞中p63结合的基因组位置是可访问的，标记为活性组蛋白修饰，并共同靶向的其他发育重要的转录调控因子。总的来说，我们的研究结果表明，p63可能积极重塑和/或影响染色质动力学在其靶位点，并在此过程中决定自己的DNA结合，可能是相邻的TF。本文的在线版本（doi：10.1186/1471-2164-15-1042）包含补充材料，可供授权用户使用。
The Transcription Factor (TF) p63 is a master regulator of epidermal development and differentiation as evident from the remarkable skin phenotype of p63 mouse knockouts. Furthermore, ectopic expression of p63 alone is sufficient to convert simple epithelium into stratified epithelial tissues in vivo and p63 is required for efficient transdifferentiation of fibroblasts into keratinocytes. However, little is known about the molecular mechanisms of p63 function, in particular how it selects its target sites in the genome. p63, which acts both as an activator and repressor of transcription, recognizes a canonical binding motif that occurs over 1 million times in the human genome. But, in human keratinocytes less than 12,000 of these sites are bound in vivo suggesting that underlying chromatin architecture and cooperating TFs mediate p63-genome interactions. We find that the chromatin architecture at p63-bound targets possess distinctive features and can be used to categorize p63 targets into proximal promoters (1%), enhancers (59%) and repressed or inactive (40%) regulatory elements. Our analysis shows that the chromatin modifications H3K4me1, H3K27me3, along with overall chromatin accessibility status can accurately predict bonafide p63-bound sites without a priori DNA sequence information. Interestingly, however there exists a qualitative correlation between the p63 binding motif and accessibility and H3K4me1 levels. Furthermore, we use a comprehensive in silico approach that leverages ENCODE data to identify several known TFs such as AP1, AP2 and novel TFs (RFX5 for e.g.) that can potentially cooperate with p63 to modulate its myriad biological functions in keratinocytes. Our analysis shows that p63 bound genomic locations in keratinocytes are accessible, marked by active histone modifications, and co-targeted by other developmentally important transcriptional regulators. Collectively, our results suggest that p63 might actively remodel and/or influence chromatin dynamics at its target sites and in the process dictate its own DNA binding and possibly that of adjacent TFs. The online version of this article (doi:10.1186/1471-2164-15-1042) contains supplementary material, which is available to authorized users.
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