Epigenetic Regulation of Skin Regional Specificity

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Summary (30 lines) The long-term objective of our research is to understand the basic principles regulating the development and regeneration of skin and its appendages, and to apply this knowledge to regenerative medicine. Recent progress in stem cell biology has allowed the production of skin substitutes which help patients suffering from severe skin injuries to survive. Yet, these skin substitutes lack regional specificities seen in human skin (e.g., scalp, face, palm, sole). The next major challenge will be to produce skins with proper region-specific phenotypes for optimal function. While studies on region-specific skin in the mouse ear, sole and human fibroblasts were carried out, no systemic studies have been made. Birds exhibit remarkable region-specific skin appendages for communication, endothermy and flight, and are accessible to experimentation. We have demonstrated how temporo-spatial expression of diffusible morphogens (Wnt, FGF, BMP and their antagonists) can mediate epidermal-dermal interactions to generate distinct skin appendage phenotypes. Yet, how these morphogens work at the epigenetic level, including upstream in the dermis and downstream in the epidermis, are mostly unknown. Several recent studies provide new clues. First, the scalp is known to be a unique skin domain with distinct appendage phenotypes in humans (terminal hairs or alopecia) and birds (crest feathers or combs). Polish chicken variants grow feathers instead of the comb on the scalp. Using genetic analyses, we showed a195 bp duplication in the non-coding region of HoxC10. This study offers new clues to study how misexpression of HoxC members can act on morphogens to change combs into feathers, and how the HoxC gene cluster is regulated. Second, using transcriptome analyses to compare dorsal and shank skin, we recently identified a group of molecular scale-feather converters. Following this clue, we performed ATAC- seq and high-order chromatin interactome studies to explore 3D genome organizations in feathers, scales, and intermediate specimens. Preliminary data reveal differential chromatin accessible regions in feather / scale inductive dermis, and in competent / committed epidermis, providing new insights into the induction of region- specific skin appendages. Thus, the time is ripe to follow these clues to advance our understanding of skin regional specification. We hypothesize that dermis in different skin regions exhibit distinct epigenetic profiles, leading to specific combinatorial morphogen expressions, which guide epidermis to form specific appendage types. In development, epidermal cells, during a time window, can exhibit bipotent competency to respond to different dermal signals and form specific appendage types. The hypothesis will be evaluated and developed further using a combination of classical tissue transplantation experiments and cutting-edge omics technologies. We will focus on the scalp, dorsal and shank skins in this study but consider the fundamental principles that would be applicable to other skin regions. The work will advance our understanding of how region-specific skin appendages are established from the morphogen level to the epigenetic level.