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, 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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