Epigenetic control of stem cell activity during epithelial tissue regeneration

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In the era of tissue engineering and the development of novel approaches for stem cell-driven organ regeneration, it is important for researchers and physicians to understand how multi-potent stem cells differentiate into specialized cell types, and why these processes are altered in pathological conditions, such as cancer, autoimmune conditions, impaired tissue regeneration, wound healing, hair loss.Adult stem cells contribute to the regeneration process of many organs in a healthy organism. The mechanisms that control stem cell activity, however, are altered in many disorders. Research into the relationship between these disorders and the changed mechanisms is, thus, an important area for biomedical research. Skin serves as an important source of adult stem cells, and several distinct adult somatic cell populations isolated from the skin were successfully employed for reprogramming and generation of induced pluripotent cells. Research into genome and chromatin biology over the last two decades has revealed that in addition to genetic mechanisms, lineage-specific gene expression programs are also regulated epigenetically, i.e., via biochemical modification of the chromatin structure. Polycomb group proteins are epigenetic regulators that operate as transcriptional repressors, compacting chromatin via enzymatic histone modifications and preventing binding of the transcription machinery to gene promoters. The polycomb group proteins play a critical role in the control of epithelial stem cell renewal and differentiation in the skin. Cbx4 as a member of Polycomb family of proteins protects epithelial stem cells from ageing in normal skin. However, its role in the control of stem cell activity during wound healing remains unclear. This proposal represents a logical continuation of productive collaboration between two laboratories currently supported by the grants from the Medical Research Council UK, National Science Foundation of China and UK-China Science Bridge Programme. This proposal will extend these studies to define the role of Polycomb repressor Cbx4 in the control of stem cell activity in the skin during wound-induced regeneration. Successful performance of this project will help in better understanding the complexity of regulatory mechanisms that control stem cell activity in regenerating epithelial tissues and in designing new approaches on how to target stem cells in the clinical conditions accompanied by their un-controlled activation/expansion or exhausting/loss.