Groucho/ transducin-like Enhancer-of- split (TLE)-dependent and -independent transcriptional regulation by Runx3.
Regulation of gene expression by tissue-specific transcription factors involves both turning on and turning off transcription of target genes. Runx3, a runt-domain transcription factor, regulates cell-intrinsic functions by activating and repressing gene expression in sensory neurons, dendritic cells (DC), and T cells. To investigate the mechanism of Runx3-mediated repression in an in vivo context, we generated mice expressing a mutant Runx3 lacking the C-terminal VWRPY, a motif required for Runx3 interaction with the corepressor Groucho/ transducin-like Enhancer-of-split ( TLE). In contrast with Runx3(-/-) mice, which displayed ataxia due to the death of dorsal root ganglia TrkC neurons, Runx3(VWRPY-/-) mice were not ataxic and had intact dorsal root ganglia neurons, indicating that ability of Runx3 to tether Groucho/ TLE is not essential for neurogenesis. In the DC compartment, the mutant protein Runx3(VWRPY-) promoted normally developed skin Langerhans cells but failed to restrain DC spontaneous maturation, indicating that this latter process involves Runx3- mediated repression through recruitment of Groucho/ TLE. Moreover, in CD8(+) thymocytes, Runx3(VWRPY-) up-regulated alphaE/ CD103-like WT Runx3, whereas unlike wild type, it failed to repress alphaE/ CD103 in CD8(+) splenocytes. Thus, in CD8-lineage T cells, Runx3 regulates alphaE/ CD103 in opposing regulatory modes and recruits Groucho/ TLE to facilitate the transition from activation to repression. Runx3(VWRPY-) also failed to mediate the epigenetic silencing of CD4 gene in CD8(+) T cells, but normally regulated other pan-CD8(+) T cell genes. These data provide evidence for the requirement of Groucho/ TLE for Runx3- mediated epigenetic silencing of CD4 and pertain to the mechanism through which other Runx3-regulated genes are epigenetically silenced.[1]References
- Groucho/transducin-like Enhancer-of-split (TLE)-dependent and -independent transcriptional regulation by Runx3. Yarmus, M., Woolf, E., Bernstein, Y., Fainaru, O., Negreanu, V., Levanon, D., Groner, Y. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
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