title: p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells.
abstract: Chromatin structural states and their remodelling, including higher-order chromatin folding and three-dimensional (3D) genome organisation, play an important role in the control of gene expression. The role of 3D genome organisation in the control and execution of lineage-specific transcription programmes during the development and differentiation of multipotent stem cells into specialised cell types remains poorly understood. Here, we show that substantial remodelling of the higher-order chromatin structure of the epidermal differentiation complex (EDC), a keratinocyte lineage-specific gene locus on mouse chromosome 3, occurs during epidermal morphogenesis. During epidermal development, the locus relocates away from the nuclear periphery towards the nuclear interior into a compartment enriched in SC35-positive nuclear speckles. Relocation of the EDC locus occurs prior to the full activation of EDC genes involved in controlling terminal keratinocyte differentiation and is a lineage-specific, developmentally regulated event controlled by transcription factor p63, a master regulator of epidermal development. We also show that, in epidermal progenitor cells, p63 directly regulates the expression of the ATP-dependent chromatin remodeller Brg1, which binds to distinct domains within the EDC and is required for relocation of the EDC towards the nuclear interior. Furthermore, Brg1 also regulates gene expression within the EDC locus during epidermal morphogenesis. Thus, p63 and its direct target Brg1 play an essential role in remodelling the higher-order chromatin structure of the EDC and in the specific positioning of this locus within the landscape of the 3D nuclear space, as required for the efficient expression of EDC genes in epidermal progenitor cells during skin development.
authors.affiliation: Centre for Skin Sciences, University of Bradford, Bradford BD7 1DP, UK.
authors.forename: Andrei N
authors.initials: AN
authors.lastname: Mardaryev
authors.forename: Michal R
authors.initials: MR
authors.lastname: Gdula
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Yarker
authors.forename: Vladimir U
authors.initials: VU
authors.lastname: Emelianov
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Emelianov
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Poterlowicz
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Sharov
authors.forename: Tatyana Y
authors.initials: TY
authors.lastname: Sharova
authors.forename: Julie A
authors.initials: JA
authors.lastname: Scarpa
authors.forename: Boris
authors.initials: B
authors.lastname: Joffe
authors.forename: Irina
authors.initials: I
authors.lastname: Solovei
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Botchkarev
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Fessing
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000378:metabolism; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D034622:RNA Interference; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D051268:GA-Binding Protein Transcription Factor; C495659:Gabpb2 protein, mouse; D036961:Matrix Attachment Region Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; C499372:SRSF2 protein, mouse; C469541:Satb1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D000068103:Serine-Arginine Splicing Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Brg1; Chromatin; Epidermis; Epigenetics; Keratinocyte; Mouse; Smarca4; Trp63; p63