title: Epigenomic comparison reveals activation of "seed" enhancers during transition from naive to primed pluripotency.
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.
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Factor
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Corradin
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: Zentner
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Saiakhova
authors.affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27709, USA.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Song
authors.affiliation: Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
authors.forename: Josh G
authors.initials: JG
authors.lastname: Chenoweth
authors.affiliation: Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKay
authors.affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27709, USA.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.affiliation: 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.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Scacheri
authors.affiliation: 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.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tesar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*