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Histone deacetylase inhibition elicits an evolutionarily conserved self-renewal program in embryonic stem cells.

ABSTRACT: Recent evidence indicates that mouse and human embryonic stem cells (ESCs) are fixed at different developmental stages, with the former positioned earlier. We show that a narrow concentration of the naturally occurring short-chain fatty acid, sodium butyrate, supports the extensive self-renewal of mouse and human ESCs, while promoting their convergence toward an intermediate stem cell state. In response to butyrate, human ESCs regress to an earlier developmental stage characterized by a gene expression profile resembling that of mouse ESCs, preventing precocious Xist expression while retaining the ability to form complex teratomas in vivo. Other histone deacetylase inhibitors (HDACi) also support human ESC self-renewal. Our results indicate that HDACi can promote ESC self-renewal across species, and demonstrate that ESCs can toggle between alternative states in response to environmental factors.

SUBMITTER: Ware CB

PROVIDER: S-EPMC2719860 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibition elicits an evolutionarily conserved self-renewal program in embryonic stem cells.

Ware Carol B CB Wang Linlin L Mecham Brigham H BH Shen Lanlan L Nelson Angelique M AM Bar Merav M Lamba Deepak A DA Dauphin Derek S DS Buckingham Brian B Askari Bardia B Lim Raymond R Tewari Muneesh M Gartler Stanley M SM Issa Jean-Pierre JP Pavlidis Paul P Duan Zhijun Z Blau C Anthony CA

Cell stem cell 20090401 4

Recent evidence indicates that mouse and human embryonic stem cells (ESCs) are fixed at different developmental stages, with the former positioned earlier. We show that a narrow concentration of the naturally occurring short-chain fatty acid, sodium butyrate, supports the extensive self-renewal of mouse and human ESCs, while promoting their convergence toward an intermediate stem cell state. In response to butyrate, human ESCs regress to an earlier developmental stage characterized by a gene exp ...[more]

PMID: 19341625

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Project description:BackgroundUnderstanding the molecular mechanisms controlling pluripotency in embryonic stem cells (ESCs) is of central importance towards realizing their potentials in medicine and science. Cross-species examination of transcriptional co-expression allows elucidation of fundamental and species-specific mechanisms regulating ESC self-renewal or differentiation.Methodology/principal findingsWe examined transcriptional co-expression of ESCs from pathways to global networks under the framework of human-mouse comparisons. Using generalized singular value decomposition and comparative partition around medoids algorithms, evolutionarily conserved and divergent transcriptional co-expression regulating pluripotency were identified from ESC-critical pathways including ACTIVIN/NODAL, ATK/PTEN, BMP, CELL CYCLE, JAK/STAT, PI3K, TGFbeta and WNT. A set of transcription factors, including FOX, GATA, MYB, NANOG, OCT, PAX, SOX and STAT, and the FGF response element were identified that represent key regulators underlying the transcriptional co-expression. By transcriptional intervention conducted in silico, dynamic behavior of pathways was examined, which demonstrate how much and in which specific ways each gene or gene combination effects the behavior transition of a pathway in response to ESC differentiation or pluripotency induction. The global co-expression networks of ESCs were dominated by highly connected hub genes such as IGF2, JARID2, LCK, MYCN, NASP, OCT4, ORC1L, PHC1 and RUVBL1, which are possibly critical in determining the fate of ESCs.Conclusions/significanceThrough these studies, evolutionary conservation at genomic, transcriptomic, and network levels is shown to be an effective predictor of molecular factors and mechanisms controlling ESC development. Various hypotheses regarding mechanisms controlling ESC development were generated, which could be further validated by in vitro experiments. Our findings shed light on the systems-level understanding of how ESC differentiation or pluripotency arises from the connectivity or networks of genes, and provide a "road-map" for further experimental investigation.

Dataset Information

Histone deacetylase inhibition elicits an evolutionarily conserved self-renewal program in embryonic stem cells.

Publications

Histone deacetylase inhibition elicits an evolutionarily conserved self-renewal program in embryonic stem cells.

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