Skin, the outermost layer of mammals, acts as a barrier to protect the body from hazards in theenvironment and to keep fluids within the body. Skin originates from a single layer of embryonic skin progenitorcells that give rise to skin lineages: the epidermis and hair follicles. In an adult organism, separate pools ofepidermal and hair follicle stem cells control skin maintenance throughout the lifespan of the animal.Identification of the molecular mechanisms that control skin morphogenesis during embryonic development, aswell as those that control the self-renewal and differentiation of skin stem cells during adulthood will enhanceour knowledge of skin biology and of the basis behind various skin disorders. My previous work revealed that a key epigenetic regulator, the Polycomb complex, represses theepidermal differentiation program and promotes the proliferation of embryonic skin progenitor cells. The centralcore of this proposal is to elucidate the roles of the Polycomb complex in the control of embryonic and adultskin stem cells. During the K99 phase, in vivo loss-of-function studies will uncover whether the Polycombcomplex is important for the establishment and maintenance of skin lineages by skin stem cells. Next, in orderto characterize the mechanism of action of this complex, biochemical approaches will be used to identifyPolycomb target genes. During the R00 phase, the roles of identified targets in the control of stem cellmaintenance and differentiation will be examined. Completion of these studies will reveal the role of thePolycomb complex in skin control and will also establish a paradigm for future studies of other epigeneticregulators. Recently, my studies have revealed differential expression patterns of additional important epigeneticregulators in embryonic skin cell progenitors and differentiated cells, suggesting an important role forepigenetic regulation in the control of skin stem cells. To characterize this epigenetic regulatory network, theroles of these epigenetic factors in the control of epidermal development will be examined during the R00phase. In vitro functional studies will reveal whether the selected epigenetic regulators control proliferation anddifferentiation of epidermal cells. The in vitro findings will be next examined in vivo by looking for epidermalreconstitution upon in utero injections of viruses that alter expression of the candidate genes or by engraftmentof overexpressing and/or knock-down cells. Finally, rigorous biochemical and molecular studies will uncoverthe mechanism of action of the epigenetic factors. In summary, the completion of these studies will unveil theroles of epigenetic regulators in the control of a tissue-skin-that is essential for our survival.

Public Health Relevance

Skin is an essential barrier that protects body against infection and dehydration. It is established and maintained by a pool of stem cells that both self-renew and differentiate into different skin cell types to form the barrier. The research in this proposal is focused on characterization of the molecular mechanisms that control the function of skin stem cells. The deep understanding of these processes will set the basis for clinical use of these cells in regenerative medicine and for developing methods for treatment of skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Transition Award (R00)
Project #
4R00AR057817-03
Application #
8207550
Study Section
Special Emphasis Panel (NSS)
Program Officer
Baker, Carl
Project Start
2011-02-15
Project End
2014-01-31
Budget Start
2011-02-15
Budget End
2012-01-31
Support Year
3
Fiscal Year
2011
Total Cost
$249,000
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Cohen, Idan; Zhao, Dejian; Bar, Carmit et al. (2018) PRC1 Fine-tunes Gene Repression and Activation to Safeguard Skin Development and Stem Cell Specification. Cell Stem Cell 22:726-739.e7
Cohen, Idan; Ezhkova, Elena (2016) Cbx4: A new guardian of p63's domain of epidermal control. J Cell Biol 212:9-11
Dauber, Katherine L; Perdigoto, Carolina N; Valdes, Victor J et al. (2016) Dissecting the Roles of Polycomb Repressive Complex 2 Subunits in the Control of Skin Development. J Invest Dermatol 136:1647-1655
Wurm, Stefanie; Zhang, Jisheng; Guinea-Viniegra, Juan et al. (2015) Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2. Genes Dev 29:144-56
Perdigoto, Carolina N; Valdes, Victor J; Bardot, Evan S et al. (2014) Epigenetic regulation of epidermal differentiation. Cold Spring Harb Perspect Med 4:
Bardot, Evan S; Valdes, Victor J; Zhang, Jisheng et al. (2013) Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells. EMBO J 32:1990-2000
Perdigoto, Carolina N; Bardot, Evan S; Ezhkova, Elena (2013) SWItching on epidermal cell fate. Cell Stem Cell 12:141-2
Perdigoto, Carolina N; Valdes, Victor J; Bardot, Evan S et al. (2012) Epigenetic regulation of skin: focus on the Polycomb complex. Cell Mol Life Sci 69:2161-2172