The B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cells.
The B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cells.
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DOI：
10.1371/journal.pone.0042350
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Boheler KR
中科院分区：
文献类型：
--
作者：
Zhan M;Riordon DR;Yan B;Tarasova YS;Bruweleit S;Tarasov KV;Li RA;Wersto RP;Boheler KR
胚胎干细胞(ESCs)具有多能性和无限的自我更新能力。尽管已经对多能性和分化进行了广泛的研究，但对自我更新的机制了解很少，被认为涉及不寻常的细胞周期、表观遗传调节因子和多能性促进转录因子。在这里，我们发现B-MYB是一种细胞周期调节的磷蛋白和转录因子，对内细胞团的形成至关重要，它是维持ESCs正常细胞周期进程和自我更新特性的转录和协同调节网络的核心。表型上，B-MYB在胚胎干细胞和诱导的多能干细胞(IPSCs)中大量表达，并且主要以低磷酸化状态存在。基因敲除B-myb导致功能性细胞周期异常，包括S、G2和M期，以及关键的细胞周期调节因子如ccnb1和plk1的表达减少。通过对对照和B-MYB缺陷细胞进行基因表达谱分析、芯片实验和综合计算分析，我们揭示了一个高度复杂的B-MYB介导的转录网络，它引导ESC自我更新。该网络包括所有细胞周期阶段的关键调控因子和表观遗传调控因子、多能性转录因子和分化决定因素。B-myb、E2F1和c-myc优先共同调控细胞周期靶基因。B-MYB还共同靶向受OCT4、SOX2和NANOG调控的基因，这些基因与干细胞分化、胚胎发育和表观遗传控制显著相关。此外，B-MYB的缺失会导致ESCs转录层次的崩溃。这些结果结合功能研究表明，B-MYB不仅控制和加速胚胎干细胞的细胞周期进程，而且有助于决定命运和维持多能干细胞的特性。
Embryonic stem cells (ESCs) are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs), and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co-regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity.
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影响因子：
8
作者：
Knight, A. S.;Notaridou, M.;Watson, R. J.
通讯作者：
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影响因子：
5.2
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作者：
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