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

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.

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Figure 1: Myc regulates genes involved in epidermal differentiation.
Figure 2: Distinct expression profile for EDC genes in response to activated c-Myc.
Figure 3: Myc determines specific regulatory networks at the EDC.
Figure 4: Sin3a causes deacetylation of c-Myc, and loss of Sin3a in skin causes increased thickness of IFE and sebaceous glands.
Figure 5: Sin3a deletion causes epidermal proliferation and differentiation.
Figure 6: Reactivation of Myc-target genes in response to Sin3a deletion.
Figure 7: Deletion of c-Myc reverts proliferation and differentiation to normal in skin lacking Sin3a.

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Acknowledgements

We thank the CRI Genomics and Bioinformatics Core Facilities. We are grateful to P. McDonel and everybody else who provided us with reagents. In particular, we thank A. Clarke for providing us with the Mycf/f mouse line and A. G. Smith for advice and comments on the manuscript. We further thank P. Humphreys, M. McLeish and N. Miller for their technical support. We acknowledge the support of the Cambridge Stem Cell Initiative, S. Evans-Freke, the ERC (DTO) and the EMBO Young Investigator Programme (DTO). This work was funded by Cancer Research UK (CR-UK) and the Medical Research Council (MRC).

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E.M.N. carried out experiments; C.L.C. carried out experiments; S.M. carried out bioinformatics analyses; S.H. carried out experiments; M.T. carried out bioinformatics analyses; S.B. carried out experiments; M.S. carried out bioinformatics analyses; J.N. provided reagents; B.K. carried out experiments; S.A.B. provided reagents; B.H. provided reagents; D.T.O. provided reagents and wrote the paper; M.F. designed the experiments and wrote the paper.

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Correspondence to Michaela Frye.

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Nascimento, E., Cox, C., MacArthur, S. et al. The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis. Nat Cell Biol 13, 1395–1405 (2011). https://doi.org/10.1038/ncb2385

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