Systems-level dynamic analyses of fate change in murine embryonic stem cells

被引：228

作者：

Lu, Rong ^{[1
]}

Markowetz, Florian ^{[2
,3
]}

Unwin, Richard D. ^{[4
]}

Leek, Jeffrey T. ^{[5
,6
]}

Airoldi, Edoardo M. ^{[2
,3
]}

MacArthur, Ben D. ^{[5
,6
,7
,8
]}

Lachmann, Alexander ^{[7
,8
]}

Rozov, Roye ^{[5
,6
]}

Ma'ayan, Avi ^{[7
,8
]}

Boyer, Laurie A. ^{[9
]}

Troyanskaya, Olga G. ^{[2
,3
]}

Whetton, Anthony D. ^{[4
]}

Lemischka, Ihor R. ^{[1
,5
,6
]}

机构：

[1] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

[2] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA

[3] Princeton Univ, Dept Comp Sci, Princeton, NJ 08544 USA

[4] Univ Manchester, Wolfson Mol Imaging Ctr,Sch Canc & Imaging Sci, Manchester Acad Hlth Sci Ctr, Stem Cell & Leukaemia Prote Lab, Manchester M20 4QL, Lancs, England

[5] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA

[6] Mt Sinai Sch Med, Black Family Stem Cell Inst, New York, NY 10029 USA

[7] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA

[8] Mt Sinai Sch Med, Syst Biol Ctr New York, New York, NY 10029 USA

[9] MIT, Dept Biol, Cambridge, MA 02139 USA

来源：

NATURE | 2009年 / 462卷 / 7271期

基金：

英国生物技术与生命科学研究理事会; 美国国家科学基金会;

关键词：

TRANSCRIPTIONAL REGULATORY CIRCUITRY; SELF-RENEWAL; GENE-EXPRESSION; NANOG; PLURIPOTENCY; NETWORK; MOUSE; CHROMATIN; OCT4; DIFFERENTIATION;

D O I：

10.1038/nature08575

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Molecular regulation of embryonic stem cell (ESC) fate involves a coordinated interaction between epigenetic(1-4), transcriptional(5-10) and translational(11,12) 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(13-15). 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 multi-layer regulatory mechanisms responsible for changes in protein expression that determine stem cell fate.

引用

页码：358 / U126

页数：7

共 37 条

[1] Getting started in probabilistic graphical models [J].