Vladimir A. Botchkarev, MD. PhD

Summary

My research laboratory was established in 1999 in Boston University. This laboratory represents a leading position in the areas of molecular control of skin development, regeneration and epigenetic regulation of gene expression (total number of articles, reviews and book chapters published – 115, H-Index – 51). Since 2001, my research is supported by the grants from the NIAMS and was recognized via several prestige awards including the Dermatology Foundation Career Development Award (2000), NIH Independent Scientist Award (2002), SID State-of-the-Art Plenary Lecture (2014), and WCHR John Ebling Keynote Lecture (2024).

The goal of our research program 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 aging, wound healing and carcinogenesis.

This is an emerging area of research in the stem cell and skin biology, and our laboratory focuses on the molecular control of the cross-talk between signaling/transcription factor-mediated and epigenetic regulatory mechanisms during execution of lineage-specific differentiation programs in the skin epithelial stem cells.

Our studies revealed that in the skin the transcription factor-dependent and epigenetic regulatory mechanisms are intimately linked to each other. We showed that p63 transcription factor, a master regulator of epidermal development, plays a novel, previously unrecognized role in regulating the expression of at least three important components of the epigenetic machinery: the ATP-dependent chromatin remodeler Brg1, the genome organizer Satb1, and Polycomb group member Cbx4. Serving as direct p63 targets, Brg1 and Satb1 promote chromatin mobility/higher order folding and coordinated gene activity in the keratinocyte-specific EDC locus during terminal differentiation in the epidermis, while Cbx4 maintains an epithelial identity and represses non-keratinocyte (neuronal, mesodermal) genes in epidermal keratinocytes.

We have recently demonstrated the essential roles for Ten-eleven translocation (TET) family enzymes, catalyzing 5-methylcytosine oxidation in DNA, in establishment of lineage-specific gene expression program and control of Dlx3/Krt25/Krt28 axis in hair follicle epithelial cells implicating a modulation of DNA methylation as a novel approach for hair growth control.

To better understand mechanisms that control stem cell aging, we used Naked Mole-Rats (NMRs), which show remarkable longevity with the duration of lifespan for over 30 years associated with resistance to a number of age-associated disorders (cancer, cardio-vascular diseases, neurodegeneration).

We established the Naked Mole-Rat facility at Boston University Animal Science Center. We showed that in contrast to human or mouse skin aging, the transcript levels of several longevity-associated and tumor-suppressor genes are increased in aged NMR skin.

We are exploring the specific features in the NMR skin transcriptome that contribute to the resistance of NMRs to scar formation during wound healing and to chemically-induced skin carcinogenesis. We believe that our research will provide a platform for further investigations of NMRs as a model organism for studying the biology and disease resistance of human skin.

Research Interests

• Molecular Control of Skin Development and Hair Growth
• Skin Aging
• Regeneration and Carcinogenesis

Selected Publications

1. V.A. Botchkarev, N.V. Botchkareva, W. Roth, M. Nakamura, L.-H. Chen, W. Herzog, G. Lindner, J.A. McMahon, C. Peters, R. Lauster, A.P. McMahon, R. Paus. Noggin is a mesenchymally-derived stimulator of hair follicle induction. Nature Cell Biol 1999, 1, 158-164. PMID: 10559902.
2. A.A.Sharov, M.Y.Fessing, R.Atoyan, T.Y.Sharova, C.Haskell-Luevano, L.Weiner, K.Funa, J.L. Brissette, B.A.Gilchrest, V.A.Botchkarev. Bone morphogenetic protein (BMP) signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor-1 pathway. Proc Natl Acad Sci USA, 2005, 102, 93-98. PMID: 15618398
3. A.A.Sharov, T.Y.Sharova, A.N.Mardariev, A. Tommasi di Vignano, R.Atoyan, L.Weiner, S. Yang, J.L. Brissette, G.P.Dotto, V.A.Botchkarev. BMP signaling controls hair follicle size and modulates the expression of cell cycle-associated genes. Proc Natl Acad Sci USA, 2006, 103, 18166-18171. PMID: 17114283
4. M.Y. Fessing, A.N. Mardaryev, M. Gdula, A.A. Sharov, T.Y. Sharova, V. Rapisarda, K.B. Gordon, A.D. Smorodchenko, K. Poterlowicz, G. Ferone, Y. Kohwi, C. Missero, T. Kohwi-Shigematsu, V.A. Botchkarev. p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis. J Cell Biol 2011, 194, 825-839. PMID: 21930775
5. Mardaryev AN, Liu B, Rapisarda V, Poterlowicz K, Malashchuk I, Rudolf J, Sharov AA, Jahoda CA, Fessing MY, Benitah SA, Xu GL, Botchkarev VA. Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium. J Cell Biol. 2016, 212:77-89. PMID:26711500
6. Fatima I, Chen G, Botchkareva NV, Sharov AA, Thornton D, Wilkinson HN, Hardman MJ, Grutzkau A, Magalhaes JP, Seluanov A, Smith ESJ, Gorbunova V, Mardaryev AN, Faulkes CG, Botchkarev VA. Skin Aging in Long-Lived Naked Mole-Rats is Accompanied by Increased Expression of Longevity-Associated and Tumor Suppressor Genes. J Invest Dermatol. 2022, 142, 2853-2863, PMID: 35691364.
7. 7. Chen GD, Fatima I, Xu Q, Rozhkova E, Fessing MY, Mardaryev AN, Sharov AA, Xu GL, Botchkarev VA. DNA dioxygenases Tet2/3 regulate gene promoter accessibility and chromatin topology in lineage-specific loci to control epithelial differentiation.  Science Advances. 2023, 13;9(2): eabo7605. PMID: 36630508.