A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal
A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal
复制标题
DOI：
10.1101/gad.1769609
复制
发表时间：
2009-04-01
影响因子：
10.5
通讯作者：
Elledge, Stephen J.
中科院分区：
文献类型：
--
作者：
Hu, Guang;Kim, Jonghwan;Elledge, Stephen J.
我们在小鼠胚胎干（ES）细胞中进行了全基因组siRNA筛选，以确定自我更新所必需的基因，并发现了148个基因，其下调导致分化。许多鉴定的基因在基因调控和/或发育中起作用，并且在ES细胞和胚胎组织中高度表达。我们进一步确定了两个转录调控因子Cnot 3和Trim 28的靶基因。我们发现Cnot 3和Trim 28与c-Myc和Zfx共同占据许多推定的基因启动子，但不与其他多能性相关转录因子共同占据。它们在自我更新转录网络中形成一个独特的模块，与Nanog，Oct 4和Sox 2形成的核心模块分开。该模块的转录靶点富集了参与细胞周期、细胞死亡和癌症的基因。这支持了这样一种观点，即控制干细胞自我更新的调控网络在某些癌症中也可能是活跃的，并可能代表新的抗癌靶点。我们的筛选涉及超过100个新的基因在ES细胞自我更新，并说明了RNAi和正向遗传学的自我更新的系统研究的力量。
We performed a genome-wide siRNA screen in mouse embryonic stem (ES) cells to identify genes essential for self-renewal, and found 148 genes whose down-regulation caused differentiation. Many of the identified genes function in gene regulation and/or development, and are highly expressed in ES cells and embryonic tissues. We further identified target genes of two transcription regulators Cnot3 and Trim28. We discovered that Cnot3 and Trim28 co-occupy many putative gene promoters with c-Myc and Zfx, but not other pluripotency-associated transcription factors. They form a unique module in the self-renewal transcription network, separate from the core module formed by Nanog, Oct4, and Sox2. The transcriptional targets of this module are enriched for genes involved in cell cycle, cell death, and cancer. This supports the idea that regulatory networks controlling self-renewal in stem cells may also be active in certain cancers and may represent novel anti-cancer targets. Our screen has implicated over 100 new genes in ES cell self-renewal, and illustrates the power of RNAi and forward genetics for the systematic study of self-renewal.