title: SOX2 co-occupies distal enhancer elements with distinct POU factors in ESCs and NPCs to specify cell state.
abstract: SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors.
authors: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors: Michael A
authors: MA
authors: Lodato
authors: Christopher W
authors: CW
authors: Ng
authors: Joseph A
authors: JA
authors: Wamstad
authors: Albert W
authors: AW
authors: Cheng
authors: Kevin K
authors: KK
authors: Thai
authors: Ernest
authors: E
authors: Fraenkel
authors: Rudolf
authors: R
authors: Jaenisch
authors: Laurie A
authors: LA
authors: Boyer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D050809:POU Domain Factors / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; D050809:POU Domain Factors; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C074066:Pou3f2 protein, mouse