生物
细胞命运测定
染色质
细胞生物学
基因表达调控
表观基因组
表观遗传学
基因调控网络
胚胎干细胞
干细胞
转录组
基因表达
重编程
转录调控
转录因子
遗传学
基因
DNA甲基化
作者
Rong Lu,Florian Markowetz,Richard D. Unwin,Jeffrey T. Leek,Edoardo M. Airoldi,Ben D. MacArthur,Alexander Lachmann,Roye Rozov,Avi Ma’ayan,Laurie A. Boyer,Olga G. Troyanskaya,Anthony D. Whetton,Ihor R. Lemischka
出处
期刊:Nature
[Springer Nature]
日期:2009-11-19
卷期号:462 (7271): 358-362
被引量:275
摘要
Molecular regulation of embryonic stem cell (ESC) fate involves a coordinated interaction between epigenetic, transcriptional and translational mechanisms. It is unclear how these different molecular regulatory mechanisms interact to regulate changes in stem cell fate. Here we present a dynamic systems-level study of cell fate change in murine ESCs following a well-defined perturbation. Global changes in histone acetylation, chromatin-bound RNA polymerase II, messenger RNA (mRNA), and nuclear protein levels were measured over 5 days after downregulation of Nanog, a key pluripotency regulator. Our data demonstrate how a single genetic perturbation leads to progressive widespread changes in several molecular regulatory layers, and provide a dynamic view of information flow in the epigenome, transcriptome and proteome. We observe that a large proportion of changes in nuclear protein levels are not accompanied by concordant changes in the expression of corresponding mRNAs, indicating important roles for translational and post-translational regulation of ESC fate. Gene-ontology analysis across different molecular layers indicates that although chromatin reconfiguration is important for altering cell fate, it is preceded by transcription-factor-mediated regulatory events. The temporal order of gene expression alterations shows the order of the regulatory network reconfiguration and offers further insight into the gene regulatory network. Our studies extend the conventional systems biology approach to include many molecular species, regulatory layers and temporal series, and underscore the complexity of the multilayer regulatory mechanisms responsible for changes in protein expression that determine stem cell fate.
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