Increased evidence suggests that epigenetic mechanisms play an important role in the control of cellular functions in living organisms and are currently considered as a driving force of the development, phenotypic plasticity and evolutionary adaptation. Evidence accumulated in recent years suggests that higher-order chromatin organization, spatial arrangement of genes and their distal regulatory elements within the nuclear space, as well as nuclear compartmentalization of chromatin-remodeling complexes and transcription machinery play an important role in controlling gene expression. Melanocytes are highly specialized, pigment-producing cells populating in the epidermis and hair follicles. Despite significant advances in melanocyte and chromatin biology, basic principles of topological organization of melanocyte-specific genes and their enhancer elements in the nucleus, as well as fundamental mechanisms controlling the remodeling of higher-order chromatin structure of these genes during active melanin production still remain unclear. We hypothesize that three-dimensional organization of key pigment genes and their enhancer elements in the nucleus and topological interactomes with other genes are functionally important for execution of pigmentary transcription program, while activation of melanin synthesis requires substantial higher-order chromatin remodeling and spatial re- arrangements of melanocyte-specific loci and their enhancer elements in the nucleus. This hypothesis will be addressed via two Specific Aims: 1) Define the genomic neighborhood and topological interactomes of pigment-specific gene loci and correlate them with nuclear positioning of the distal enhancer elements in melanocytes;2) Delineate the role of ATP- dependent chromatin remodeler BRG1 in the control of organization of topological interactomes for lineage-specific genes and their enhancer elements in melanocytes. Thus, this exploratory project will provide important background for further research on how topological organization on melanogenic genes in the nucleus is altered in pigmentation disorders associated either with melanocyte loss (vitiligo), or expansion (melanoma). These data will also be helpful for designing new approaches for pharmacological correction of pigmentary disorders based on modulation of higher-order chromatin structure and remodeling.
Pigmentation is a process of melanin synthesis in highly specialized cells called melanocytes. Pigmentary disorders, such as melanoma, vitiligo, hair grain and others, represent a significant problem for the society, and knowledge of the pathobiological mechanisms underlying their development is highly important for the design of novel approaches for their treatment. The goal of the study to investigate how spatial arrangement of pigment genes in the nucleus is important for establishment of melanocyte- specific gene expression program and pigment production.
|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|
|Lewis, Christopher J; Mardaryev, Andrei N; Sharov, Andrey A et al. (2014) The Epigenetic Regulation of Wound Healing. Adv Wound Care (New Rochelle) 3:468-475|
|Ahmed, Mohammed I; Alam, Majid; Emelianov, Vladimir U et al. (2014) MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway. J Cell Biol 207:549-67|
|Mardaryev, Andrei N; Gdula, Michal R; Yarker, Joanne L et al. (2014) p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells. Development 141:101-11|
|Gdula, Michal R; Poterlowicz, Krzysztof; Mardaryev, Andrei N et al. (2013) Remodeling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis. J Invest Dermatol 133:2191-201|
|Botchkarev, Vladimir A; Gdula, Michal R; Mardaryev, Andrei N et al. (2012) Epigenetic regulation of gene expression in keratinocytes. J Invest Dermatol 132:2505-21|