Transcriptional functions of the corepressor Sin3A in skin
University of Cambridge
Department of Physiology, Development and Neuroscience
Wellcome Trust Medical Research Council Stem Cell Institute
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Cox, C. (2013). Transcriptional functions of the corepressor Sin3A in skin (doctoral thesis). https://doi.org/10.17863/CAM.16337
Upon activation in epidermal stem cells, the proto-oncogene c-Myc triggers their exit from the stem cell compartment resulting in an increase in progenitor cell proliferation and an induction in terminal differentiation. Whether c-Myc plays a direct transcriptional role in epidermal stem cell differentiation was unknown. The exploration of c-Myc's transcriptional roles at the epidermal differentiation complex (EDC), a locus essential for skin maturation demonstrated that binding of c-Myc to the EDC can simultaneously recruit and displace specific sets of differentiation-specific transcriptional regulators to EDC genes. Among these factors, Sin3A acts as a transcriptional co-repressor and was initially discovered via its direct interaction with Mxi1 and Mxd1, which are antagonists of the Myc family network. As such, I concentrated on the role of Sin3A as a potential opposing factor to c-Myc activity in the epidermis. To analyse the role of Sin3A in regulating epidermal stem cell fate in vivo, I generated a number of transgenic mouse models. To determine whether Sin3A functions in hair follicle stem cells, I inducibly deleted Sin3A in the hair follicle bulge, where quiescent stem cells reside. However, lack of Sin3A in the hair bulge did not cause any aberrant phenotype and I concluded that Sin3A is dispensable for hair follicle homeostasis. I next analysed a mouse model in which Sin3A is inducibly deleted in the basal layer of the epidermis. Deletion of Sin3A resulted in a severe disruption of epidermal homeostasis-namely due to increases in proliferation and differentiation. Further investigation demonstrated that this phenotype is driven by enhanced genomic recruitment of c-Myc to the epidermal differentiation complex and reactivation of c-Myc target genes involved in cellular proliferation. I found that Sin3A causes de-acetylation of the c-Myc protein to directly repress c-Myc’s transcriptional activity and is antagonistic to c-Myc in the interfollicular epidermis. I hypothesised that simultaneous deletion of Sin3A and c-Myc might return the skin to normality. Indeed, when Sin3A and Myc are concurrently deleted, proliferation and differentiation levels returned to normal. These results demonstrate how levels of Sin3A and c-Myc must be carefully balanced for epidermal homeostasis to be maintained. Decreased expression of Sin3A has been linked to tumour susceptibility in other tissues for example in non-small cell lung carcinoma making Sin3A a candidate tumour suppressor gene. I therefore considered that loss of Sin3A may lead to increased susceptibility to skin cancer. To investigate this I performed pilot experiments using UVB irradiation of skin that has one copy of Sin3A deleted in the basal layer of the epidermis. Under normal conditions, these mice have no identifiable phenotype, but pilot experiments demonstrated that after short term and long term UVB irradiation, they exhibit increased epidermal thickness and proliferation relative to controls. This recapitulated the phenotype observed when Sin3A is inducibly deleted in the interfollicular epidermis and further demonstrates the role of SinA as an inhibitor of proliferation in this tissue. Overall, these results demonstrate that an interplay between the opposing functions of Sin3A and c-Myc are necessary to ensure that there is balanced homeostasis in the interfollicular epidermis.
Sin3A, Myc, Skin, Epidermal stem cells
This work was supported by a Medical Research Council Capacity Build studentship.
This record's DOI: https://doi.org/10.17863/CAM.16337