title: Otx2 and Oct4 drive early enhancer activation during embryonic stem cell transition from naive pluripotency.
abstract: Embryonic stem cells (ESCs) are unique in that they have the capacity to differentiate into all of the cell types in the body. We know a lot about the complex transcriptional control circuits that maintain the naive pluripotent state under self-renewing conditions but comparatively less about how cells exit from this state in response to differentiation stimuli. Here, we examined the role of Otx2 in this process in mouse ESCs and demonstrate that it plays a leading role in remodeling the gene regulatory networks as cells exit from ground state pluripotency. Otx2 drives enhancer activation through affecting chromatin marks and the activity of associated genes. Mechanistically, Oct4 is required for Otx2 expression, and reciprocally, Otx2 is required for efficient Oct4 recruitment to many enhancer regions. Therefore, the Oct4-Otx2 regulatory axis actively establishes a new regulatory chromatin landscape during the early events that accompany exit from ground state pluripotency.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Shen-Hsi
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK.
authors.forename: Tüzer
authors.initials: T
authors.lastname: Kalkan
authors.affiliation: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Morissroe
authors.affiliation: Department of Molecular Biology, Faculty of Science, Raboud Institute for Molecular Life Sciences, Radboud University, 6525GA Nijmegen, the Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Marks
authors.affiliation: Department of Molecular Biology, Faculty of Science, Raboud Institute for Molecular Life Sciences, Radboud University, 6525GA Nijmegen, the Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Stunnenberg
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK.
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
authors.affiliation: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK. Electronic address: a.d.sharrocks@manchester.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Sharrocks
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051857:Otx Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050814:Octamer Transcription Factor-3; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C494174:Pou5f1 protein, mouse