The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis.
Nascimento, Elisabete M
Blanco Benavente, Sandra
Benitah, Salvador Aznar
Nature cell biology
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Nascimento, E. M., Cox, C. L., MacArthur, S., Hussain, S., Trotter, M., Blanco Benavente, S., Suraj, M., et al. (2011). The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis.. Nature cell biology, 13 (12), 1395-1405. https://doi.org/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.
Epidermis, Keratinocytes, Animals, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Mice, Proto-Oncogene Proteins c-myc, Repressor Proteins, Transcription, Genetic, Homeostasis, Female, Male, Feedback, Physiological, Sin3 Histone Deacetylase and Corepressor Complex, Primary Cell Culture, Epidermal Cells
Cancer Research UK (A7989)
Cancer Research UK (A7006)
Wellcome Trust (098021/Z/11/Z)
European Research Council (202218)
External DOI: https://doi.org/10.1038/ncb2385
This record's URL: https://www.repository.cam.ac.uk/handle/1810/301550
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