ΔNp63α represses anti-proliferative genes via H2A.Z deposition
ΔNp63α represses anti-proliferative genes via H2A.Z deposition
复制标题
DOI：
10.1101/gad.198069.112
复制
发表时间：
2012-10-15
影响因子：
10.5
通讯作者：
Espinosa, Joaquin M.
中科院分区：
文献类型：
--
作者：
Gallant-Behm, Corrie L.;Ramsey, Matthew R.;Espinosa, Joaquin M.
Delta Np 63 α是p53转录因子家族的成员，在鳞状细胞癌（SCC）中作为癌基因起作用。由于Delta Np 63 α和p53结合几乎相同的DNA序列基序，因此已经提出Delta Np 63 α作为p53的显性负抑制剂发挥作用以促进增殖和阻断凋亡。然而，大多数SCC同时过表达Δ Np 63 α和Δ Np 53，表明这些致癌事件的自主作用。在这里，我们报告发现了一种新的机制，转录抑制三角洲Np 63 α，调和这些意见。我们发现，虽然这两种蛋白质结合相同的基因组位点，他们调节很大程度上不重叠的基因集。激活后，p53结合所有增强子，而不管Delta Np 63 α状态如何，但不能反式激活被Delta Np 63 α抑制的基因。我们发现Delta Np 63 α与参与H2 A/H2A.Z交换的SRCAP染色质调节复合物相关，并介导H2A.Z在其靶位点的沉积。有趣的是，SRCAP亚基或H2A.Z的敲低导致Delta Np 63 α抑制基因的特异性诱导。我们将SAMD 9 L鉴定为受Δ Np 63 α和H2 A. Z抑制的关键抗增殖基因，其耗尽足以逆转由Δ Np 63 α敲低引起的停滞表型。总的来说，这些结果阐明了一个分子途径，有助于自主致癌作用的德尔塔Np 63 α。
Delta Np63 alpha is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because Delta Np63 alpha and p53 bind virtually identical DNA sequence motifs, it has been proposed that Delta Np63 alpha functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress Delta Np63 alpha and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mechanism of transcriptional repression by Delta Np63 alpha that reconciles these observations. We found that although both proteins bind the same genomic sites, they regulate largely nonoverlapping gene sets. Upon activation, p53 binds all enhancers regardless of Delta Np63 alpha status but fails to transactivate genes repressed by Delta Np63 alpha. We found that Delta Np63 alpha associates with the SRCAP chromatin regulatory complex involved in H2A/H2A.Z exchange and mediates H2A.Z deposition at its target loci. Interestingly, knockdown of SRCAP subunits or H2A.Z leads to specific induction of Delta Np63 alpha-repressed genes. We identified SAMD9L as a key anti-proliferative gene repressed by Delta Np63 alpha and H2A.Z whose depletion suffices to reverse the arrest phenotype caused by Delta Np63 alpha knockdown. Collectively, these results illuminate a molecular pathway contributing to the autonomous oncogenic effects of Delta Np63 alpha.