Higher-order chromatin remodeling and regulation of pigmentation

Boston University Medical Campus, Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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.