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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Nascimento, Elisabete M 
Cox, Claire L 
MacArthur, Stewart 
Hussain, Shobbir 
Trotter, Matthew 

Abstract

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.

Description

Keywords

Animals, Epidermal Cells, Epidermis, Feedback, Physiological, Female, Homeostasis, Keratinocytes, Kruppel-Like Factor 4, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Primary Cell Culture, Proto-Oncogene Proteins c-myc, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex, Transcription, Genetic

Journal Title

Nat Cell Biol

Conference Name

Journal ISSN

1465-7392
1476-4679

Volume Title

13

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Medical Research Council (G0800784)
Medical Research Council (G0801904)
Cancer Research Uk (None)
Cancer Research Uk (None)
Wellcome Trust (098021/Z/11/Z)
European Research Council (202218)