The long-term goal of this multi-disciplinary project is to understand how epithelial stem cells in the skin establish distinct patterns of gene activation and silencing during their differentiation into specialized cell lineages and how these genetic programs are re-organized during skin regeneration and aging. Recent data revealed that in addition to signaling/transcription factor-dependent regulatory mechanisms, lineage-specific gene expression programs are also regulated epigenetically, i.e., via modulation of covalent DNA/histone modifications, as well as through higher-order chromatin remodeling and establishment of long- range associations or interactomes between the genes and their enhancer elements in 3D nuclear space. In normal differentiating cells, lineage-specific long-range chromatin interactions provide structural frameworks for cell-specific transcription or silencing. Importantly, these interactions are substantially re- organized during cell transition towards malignancy, while genes located closely in topologically associated chromatin domains frequently serve as sites for chromosomal translocations in cancers. Our recent studies revealed that during skin development, transcription factor-dependent and epigenetic regulatory mechanisms are intimately linked to each other via p63 transcription factor, which plays a novel, previously unrecognized role in regulation of expression of chromatin remodeling genes Satb1 and Brg1. In this proposal, we will further address a fundamental biological problem on how epigenetic machinery operates in concert with p63 transcription master regulator to control gene expression in skin epithelial stem cells during their differentiation in specialized (epidermal, har follicle) cell lineages. In particular, we will elucidate how higher-order chromatin remodeling associated with gene activation and silencing is controlled and how functional interactomes between the genes and their enhancer elements or other genes are formed in the keratinocytes during terminal differentiation. These questions will be addressed via two Specific Aims: 1. Define a role of p63 and its target genes Brg1 and Satb1 in the control of higher-order chromatin remodeling and topological interactomes of the lineage-specific genes and their enhancer elements in skin epithelial stem cells and their progenies. 2. Identify the role of p63 and its target Polycomb Cbx4 gene in the control of formation of the repressive chromatin compartments to silence non-keratinocyte lineage genes and selected cell cycle- associated genes in epithelial stem cells and their progenies. This project will have a fundamental impact on our current knowledge of epigenetic mechanisms that regulate genome reorganization in stem cells during their differentiation in the skin and will promote the progress towards the development of novel epigenetic drugs as new paradigm for treatment of skin disorders.

Public Health Relevance

Skin homeostasis is maintained by tightly coordinated mechanisms that regulate activity and differentiation of stem cells. These mechanisms are altered in many pathological conditions associated with either stem cell expansion (cancer, autoimmunity) or loss (impaired tissue regeneration, hair loss, etc.). Information generated by this project will help to better understand epigenetic mechanisms that control stem cell activity i the skin and will provide new opportunities for therapeutic interventions to cure many skin pathological conditions, including chronic epithelial wounds, skin cancers, specific forms of hair loss, which will ultimately contribute to the enhancement of quality of life.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Baker, Carl
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Boston University
Schools of Medicine
United States
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Rapisarda, Valentina; Malashchuk, Igor; Asamaowei, Inemo E et al. (2017) p63 Transcription Factor Regulates Nuclear Shape and Expression of Nuclear Envelope-Associated Genes in Epidermal Keratinocytes. J Invest Dermatol 137:2157-2167
Kitagawa, Yohko; Ohkura, Naganari; Kidani, Yujiro et al. (2017) Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat Immunol 18:173-183
Botchkarev, Vladimir A (2017) The Molecular Revolution in Cutaneous Biology: Chromosomal Territories, Higher-Order Chromatin Remodeling, and the Control of Gene Expression in Keratinocytes. J Invest Dermatol 137:e93-e99
Poterlowicz, Krzysztof; Yarker, Joanne L; Malashchuk, Igor et al. (2017) 5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells. PLoS Genet 13:e1006966
Mardaryev, Andrei N; Liu, Bo; Rapisarda, Valentina et al. (2016) Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium. J Cell Biol 212:77-89
Botchkarev, Vladimir A; Mardaryev, Andrei N (2016) Repressing the Keratinocyte Genome: How the Polycomb Complex Subunits Operate in Concert to Control Skin and Hair Follicle Development. J Invest Dermatol 136:1538-1540
Hao, Bingtao; Naik, Abani Kanta; Watanabe, Akiko et al. (2015) An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development. J Exp Med 212:809-24
Botchkarev, Vladimir A (2015) Integration of the Transcription Factor-Regulated and Epigenetic Mechanisms in the Control of Keratinocyte Differentiation. J Investig Dermatol Symp Proc 17:30-2