The opposing transcriptional functions of Sin3A and c-Myc are required to maintain tissue homeostasis

How the proto-oncogene c-Myc balances the processes of stem cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Myc’s transcriptional roles at the Epidermal Differentiation Complex (EDC) a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovo1-1) and displace (C/EBPα, Mxi1 and Sin3A) specific sets of differentiation-specific transcriptional regulators to EDC genes. We found that Sin3A causes de-acetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3A, genomic recruitment of c-Myc to the EDC is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3A reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis via a negative feedback loop.