Groucho/transducin-like enhancer-of-split (TLE)-dependent and -independent transcriptional regulation by Runx3

Abstract

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, Runx3VWRPY-/- 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 Runx3VWRPY- 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, Runx3VWRPY- up-regulated αE/CD103-like WT Runx3, whereas unlike wild type, it failed to repress αE/CD103 in CD8+ splenocytes. Thus, in CD8-lineage T cells, Runx3 regulates αE/CD103 in opposing regulatory modes and recruits Groucho/TLE to facilitate the transition from activation to repression. Runx3VWRPY- 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. © 2006 by The National Academy of Sciences of the USA.