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

Lu, Rong; Markowetz, Florian; Unwin, Richard D.; Leek, Jeffrey T.; Airoldi, Edoardo M.; MacArthur, Ben D.; Lachmann, Alexander; Rozov, Roye; Ma’ayan, Avi; Boyer, Laurie A.; Troyanskaya, Olga G.; Whetton, Anthony D.; Lemischka, Ihor R.

doi:10.1038/nature08575

Cited by 283 publications

(284 citation statements)

References 37 publications

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“…Whether this observation is valid in other cell types is not known. A recent study on embryonic stem cells revealed that changes in protein levels are not accompanied by changes in corresponding mRNAs, although this study did not discern translational and post-translational control 38 .…”

Section: Discussioncontrasting

confidence: 79%

Global quantification of mammalian gene expression control

Schwanhäußer

Busse

et al. 2011

Nature

5,705

346

5,462

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SummaryGene expression is a multistep process that involves transcription, translation and turnover of mRNAs and proteins. Although it is one of the most fundamental processes of life, the entire cascade has never been quantified on a genome-wide scale. Here, we simultaneously measured mRNA and protein abundance and turnover by parallel metabolic pulse labeling for more than 5,000 genes in mammalian cells. While mRNA and protein levels correlated better than previously thought, corresponding half-lives showed no correlation. Employing a quantitative model we obtain the first genome-scale prediction of synthesis rates of mRNAs and proteins. We find that the cellular abundance of proteins is predominantly controlled at the level of translation. Genes with similar combinations of mRNA and protein stabilities shared functional properties, suggesting that half-lives evolved under energetic and dynamic constraints. Quantitative information about all stages of gene expression obtained in this study provides a rich resource and helps understanding the underlying design principles.

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Section: Discussioncontrasting

confidence: 79%

Global quantification of mammalian gene expression control

Schwanhäußer

Busse

et al. 2011

Nature

5,705

346

5,462

View full text Add to dashboard Cite

show abstract

“…mRNA translation, which is low in undifferentiated embryonic stem cells (ESCs) and multipotent somatic stem cells (e.g., hematopoietic stem cells and skin stem cells), increases significantly during differentiation (3)(4)(5). Importantly, genome-wide analysis of the transcriptome vs. proteome of ESCs during the early stages of differentiation demonstrated that protein levels correlate poorly with mRNA levels (Pearson's R < 0.4), underscoring the importance of posttranscriptional regulation in ESC differentiation (6).…”

mentioning

confidence: 99%

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Tahmasebi

Jafarnejad

Tam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tractbinding protein 1 (PTBP1) promotes the retention of an intron in the 5′-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.mRNA translation | 4E-BPs | PTBP | embryonic stem cell | YY2

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“…Given this switch in expression of the two topo II isozymes when cells transit from actively dividing, pluripotent state to a postmitotic, terminally differentiated state, we were tempted to investigate the stem cell-specific function of TOP2a as well as similarities and differences in targets with TOP2b. Furthermore, given a plethora of factors that are being implicated in the regulation of stem cell pluripotency and differentiation [19][20][21][22][23][24] , we were interested to uncover how these crucial enzymes contribute to this process.…”

mentioning

confidence: 99%

Gene regulation and priming by topoisomerase IIα in embryonic stem cells

et al. 2013

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Topoisomerases resolve torsional stress, while their function in gene regulation, especially during cellular differentiation, remains unknown. Here we find that the expression of topo II isoforms, topoisomerase IIa and topoisomerase IIb, is the characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, topoisomerase IIa preferentially occupies active gene promoters. Topoisomerase IIa inhibition compromises genomic integrity, which results in epigenetic changes, altered kinetics of RNA Pol II at target promoters and misregulated gene expression. Common targets of topoisomerase IIa and topoisomerase IIb are housekeeping genes, while unique targets are involved in proliferation/ pluripotency and neurogenesis, respectively. Topoisomerase IIa targets exhibiting bivalent chromatin resolve upon differentiation, concomitant with their activation and occupancy by topoisomerase IIb, features further observed for long genes. These long silent genes display accessible chromatin in embryonic stem cells that relies on topoisomerase IIa activity. These findings suggest that topoisomerase IIa not only contributes to stem-cell transcriptome regulation but also primes developmental genes for subsequent activation upon differentiation.

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

Cited by 283 publications

References 37 publications

Global quantification of mammalian gene expression control

Global quantification of mammalian gene expression control

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Gene regulation and priming by topoisomerase IIα in embryonic stem cells

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