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.
Yarmus
Merav
M
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Woolf
Eilon
E
Bernstein
Yael
Y
Fainaru
Ofer
O
Negreanu
Varda
V
Levanon
Ditsa
D
Groner
Yoram
Y
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D050677:Core Binding Factor Alpha 3 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D039001:Integrin alpha Chains; D012097:Repressor Proteins; C493730:Runx3 protein, mouse; C091367:alpha E integrins; C091023:gro protein, Drosophila