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Cell Stem Cell. 2019 Feb 7;24(2):271-284.e8. doi: 10.1016/j.stem.2018.12.012. Epub 2019 Jan 24.

TFAP2C- and p63-Dependent Networks Sequentially Rearrange Chromatin Landscapes to Drive Human Epidermal Lineage Commitment.

Author information

1
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Statistics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA 94305, USA; CEMS, NCMIS, MDIS, Academy of Mathematics & Systems Science, Chinese Academy of Sciences, Beijing 100080, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
3
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Department of Statistics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA 94305, USA; CEMS, NCMIS, MDIS, Academy of Mathematics & Systems Science, Chinese Academy of Sciences, Beijing 100080, China.
7
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
8
CEMS, NCMIS, MDIS, Academy of Mathematics & Systems Science, Chinese Academy of Sciences, Beijing 100080, China.
9
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA 94305, USA.
10
Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
11
Department of Statistics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA 94305, USA.
12
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: oro@stanford.edu.

Abstract

Tissue development results from lineage-specific transcription factors (TFs) programming a dynamic chromatin landscape through progressive cell fate transitions. Here, we define epigenomic landscape during epidermal differentiation of human pluripotent stem cells (PSCs) and create inference networks that integrate gene expression, chromatin accessibility, and TF binding to define regulatory mechanisms during keratinocyte specification. We found two critical chromatin networks during surface ectoderm initiation and keratinocyte maturation, which are driven by TFAP2C and p63, respectively. Consistently, TFAP2C, but not p63, is sufficient to initiate surface ectoderm differentiation, and TFAP2C-initiated progenitor cells are capable of maturing into functional keratinocytes. Mechanistically, TFAP2C primes the surface ectoderm chromatin landscape and induces p63 expression and binding sites, thus allowing maturation factor p63 to positively autoregulate its own expression and close a subset of the TFAP2C-initiated surface ectoderm program. Our work provides a general framework to infer TF networks controlling chromatin transitions that will facilitate future regenerative medicine advances.

PMID:
30686763
DOI:
10.1016/j.stem.2018.12.012

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