The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis

• Published in: Nature cell biology Vol. 13; no. 12; pp. 1395 - 1405
• Main Authors: Nascimento, Elisabete M., Cox, Claire L., MacArthur, Stewart, Hussain, Shobbir, Trotter, Matthew, Blanco, Sandra, Suraj, Menon, Nichols, Jennifer, Kübler, Bernd, Benitah, Salvador Aznar, Hendrich, Brian, Odom, Duncan T., Frye, Michaela
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2011; Nature Publishing Group
• Subjects: 631/337/572; 631/553/2711; 631/80; Animals; Biomedical and Life Sciences; Cancer; Cancer Research; Cell Biology; Cell growth; Developmental Biology; Epidermal Cells; Epidermis - physiology; Feedback, Physiological - physiology; Female; Genetic transcription; Homeostasis; Homeostasis - genetics; Keratinocytes - cytology; Keratinocytes - physiology; Kruppel-Like Factor 4; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Primary Cell Culture; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Repressor Proteins - genetics; Repressor Proteins - physiology; Research parks; Sin3 Histone Deacetylase and Corepressor Complex; Stem Cells; Tissues; Transcription, Genetic - physiology; United Kingdom; United Kingdom > UK
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2385

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, a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovol-1) and displace (Cebpa, Mxi1 and Sin3a) specific sets of differentiation-specific transcriptional regulators to epidermal differentiation complex genes. We found that Sin3a causes deacetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3a, genomic recruitment of c-Myc to the epidermal differentiation complex 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 through a negative feedback loop. The transcriptional role of c-Myc in maintaining tissue homeostasis is still unclear. Using mice conditionally expressing an activated form of c-Myc in the epidermis, and genome-wide approaches, Frye and colleagues show that c-Myc modulates the expression of the epidermal differentiation complex locus in the skin by displacing or recruiting specific transcriptional regulators. c-Myc activity is negatively regulated in vivo in this context by Sin3a.