Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.
Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.
复制标题
DOI：
10.1371/journal.pgen.1005053
复制
发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Narita M
中科院分区：
文献类型：
--
作者：
Kirschner K;Samarajiwa SA;Cairns JM;Menon S;Pérez-Mancera PA;Tomimatsu K;Bermejo-Rodriguez C;Ito Y;Chandra T;Narita M;Lyons SK;Lynch AG;Kimura H;Ohbayashi T;Tavaré S;Narita M
DNA结合的抑癌基因P53的下游功能因细胞环境而异，P53的持续激活最近被认为与肿瘤抑制和衰老有关。然而，关于p53靶基因调控的全基因组信息大多来自急性遗传毒性条件。利用芯片序列和表达数据，我们发现急性激活(通过DNA损伤)和长期激活(在衰老或促凋亡条件下)的p53之间存在明显的结合谱。与经典的“急性”P53结合谱相比，“慢性”P53峰与CpG岛密切相关。此外，P53的慢性CpG岛结合在衰老和促凋亡条件下提供了不同的表达模式。使用在慢性病中看到的P53靶点以及外部的高通量数据集，我们已经建立了P53网络，揭示了广泛的自我调节的“P53枢纽”，在那里P53和许多P53靶标可以物理上相互作用。将这些结果与公共临床数据结合起来，确定了与癌症相关的造脂酶SCD，我们发现该酶通过CpG岛启动子直接受到p53的抑制，从而在p53和癌症的一个标志-“造脂表型”之间提供了一种机制联系。我们的数据揭示了慢性P53靶标的不同表型关联，这是特定基因调控机制的基础。P53转录因子是一种频繁突变的肿瘤抑制因子，有助于修复或消除受损细胞。P53的水平通常是通过其稳定性来调节的；它不断地产生和降解，因此在应激时，P53迅速上调。这种急性诱导的p53已被用作研究全基因组p53靶点的主要模型系统。然而，新出现的证据表明，持续激活的p53与癌症相关的表型有关，如细胞衰老。我们研究了通过DNA损伤急性诱导的P53以及在癌基因诱导的衰老和促凋亡状态下慢性激活的P53对全基因组的基因调控。有趣的是，急性和慢性P53 DNA结合谱高度不同，后者优先与更大和相对开放的启动子相关，称为CpG岛。此外，我们对P53依赖的基因表达和P53结合的基因组DNA图谱的综合分析表明，P53及其许多靶点在慢性病中形成广泛的自我调节中心，在那里他们可以物理上相互作用。这些数据不仅大大扩展了P53直接靶点的列表，而且突出了慢性P53独特的基因调控。最后，我们证明了癌症相关的造脂酶，硬脂酰辅酶A去饱和酶，在慢性疾病中通过其CpG岛启动子是一个真正的P53抑制靶点。
The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical ‘acute’ p53 binding profile, ‘chronic’ p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory ‘p53 hubs’ where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the ‘lipogenic phenotype’, a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms. The p53 transcription factor is a frequently mutated tumour suppressor that contributes to repairing or eliminating damaged cells. Levels of p53 are typically regulated through its stability; it is constantly produced and degraded, so that upon stress, p53 is up-regulated quickly. This acutely induced p53 has been used as a major model system for studying genome-wide p53 targets. However, emerging evidence suggests that persistently activated p53 is involved in cancer-associated phenotypes, such as cellular senescence. We investigate genome-wide gene regulation by acutely induced p53 through DNA damage as well as chronically activated p53 in oncogene-induced senescence and pro-apoptotic states. Interestingly, acute and chronic p53 DNA binding profiles are highly distinctive, the latter being preferentially associated with larger and relatively open promoters called CpG islands. Furthermore, our integrative analyses of both p53-dependent gene expression and p53-binding genomic DNA profiles reveal that p53 and many of its targets in chronic conditions form extensive self-regulatory hubs, where they can physically interact. The data not only substantially extend the list of direct p53 targets but highlight unique gene regulation by chronic p53. Finally we show that the cancer-associated lipogenic enzyme, stearoyl-CoA desaturase, is a bona fide p53-repressive target through its CpG island promoter in chronic conditions.
登录
查看更多内容
影响因子：
14.9
作者：
Chatr-Aryamontri A;Breitkreutz BJ;Heinicke S;Boucher L;Winter A;Stark C;Nixon J;Ramage L;Kolas N;O'Donnell L;Reguly T;Breitkreutz A;Sellam A;Chen D;Chang C;Rust J;Livstone M;Oughtred R;Dolinski K;Tyers M
通讯作者：
Tyers M
影响因子：
16
作者：
Chandra, Tamir;Kirschner, Kristina;Thuret, Jean-Yves;Pope, Benjamin D.;Ryba, Tyrone;Newman, Scott;Ahmed, Kashif;Samarajiwa, Shamith A.;Salama, Rafik;Carroll, Thomas;Stark, Rory;Janky, Rekin's;Narita, Masako;Xue, Lixiang;Chicas, Agustin;Nunez, Sabrina;Janknecht, Ralf;Hayashi-Takanaka, Yoko;Wilson, Michael D.;Marshall, Aileen;Odom, Duncan T.;Babu, M. Madan;Bazett-Jones, David P.;Tavare, Simon;Edwards, Paul A. W.;Lowe, Scott W.;Kimura, Hiroshi;Gilbert, David M.;Narita, Masashi
通讯作者：
Narita, Masashi
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
15.9
作者：
Glinsky, GV;Glinskii, AB;Gerald, WL
通讯作者：
Gerald, WL
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA