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Cell Stem Cell. 2014 Jun 5;14(6):854-63. doi: 10.1016/j.stem.2014.05.005.

Epigenomic comparison reveals activation of "seed" enhancers during transition from naive to primed pluripotency.

Author information

1
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
2
Institute for Genome Sciences & Policy, Duke University, Durham, NC 27709, USA.
3
Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
4
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: peter.scacheri@case.edu.
5
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; National Center for Regenerative Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: paul.tesar@case.edu.

Abstract

Naive mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and that these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naive-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naive pluripotency to a somatic regulatory program.

PMID:
24905169
PMCID:
PMC4149284
DOI:
10.1016/j.stem.2014.05.005
[Indexed for MEDLINE]
Free PMC Article

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