Regulation of the dynamic chromatin architecture of the epidermal differentiation complex is mediated by a c-Jun/AP-1-modulated enhancer.
The epidermal differentiation complex (EDC) locus comprises a syntenic and linear cluster of genes whose concomitant expression is a hallmark feature of differentiation in the developing skin epidermis. Many of the EDC proteins are cross-linked together to form the cornified envelope, an essential and discrete unit of the mammalian skin barrier. The mechanism underlying coordinate transcriptional activation of the EDC is unknown. Within the human EDC, we identified an epidermal-specific regulatory enhancer, 923, which responded to the developmental and spatiotemporal cues at the onset of epidermal differentiation in the mouse embryo. Comparative chromosomal conformation capture assays in proliferating and differentiated primary mouse keratinocytes revealed multiple physiologically sensitive chromatin interactions between the 923 enhancer and EDC gene promoters, thus depicting the dynamic chromatin topology of the EDC. We elucidate a mechanistic link between c-Jun/AP-1 and 923, whereby AP-1- and 923-mediated EDC chromatin remodeling are required for functional EDC gene activation. Thus, we identify a critical enhancer/transcription factor axis governing the dynamic regulation of the EDC chromatin architecture and gene expression and provide a framework for future studies toward understanding gene regulation in cutaneous diseases.
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Inez Y
IY
Oh
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Danielle M
DM
Albea
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Zane A
ZA
Goodwin
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Ashley M
AM
Quiggle
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Breeana P
BP
Baker
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Ann M
AM
Guggisberg
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Jessica H
JH
Geahlen
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA.
Grace M
GM
Kroner
Division of Dermatology, Department of Internal Medicine, Center for Pharmacogenomics, Center for the Study of Itch, Washington University School of Medicine, St Louis, Missouri, USA. Electronic address: cstrong@dom.wustl.edu.
Cristina
C
de Guzman Strong
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D007763:Lac Operon; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D005810:Multigene Family / Q000235:genetics; D011247:Pregnancy; D012313:RNA / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism
D002843:Chromatin; D018808:Transcription Factor AP-1; D012313:RNA