Dataset Information

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, 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.

SUBMITTER: Yarmus M

PROVIDER: S-EPMC1464349 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Yarmus Merav M Woolf Eilon E Bernstein Yael Y Fainaru Ofer O Negreanu Varda V Levanon Ditsa D Groner Yoram Y

Proceedings of the National Academy of Sciences of the United States of America 20060501 19

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 Run ...[more]

PMID: 16651517

Similar Datasets

Project description:BACKGROUND: The full-length mammalian homologs of groucho, Tle1, 2, 3, and 4, act as transcriptional corepressors and are recruited by transcription factors containing an eh1 or WRPW/Y domain. Many transcription factors critical to pancreas development contain a Gro/TLE interaction domain and several have been shown to require Gro/TLE interactions for proper function during neuronal development. However, a detailed analysis of the expression patterns of the Gro/TLE proteins in pancreas development has not been performed. Moreover, little is known about the ability of Gro/TLE proteins to interact with transcription factors in the pancreas. RESULTS: We describe the expression of Gro/TLE family members, and of 34 different transcription factors that contain a Gro/TLE interaction motif, in the pancreas utilizing nine SAGE libraries created from the developing and adult pancreas, as well as the GenePaint database. Next, we show the dynamic expression of Tle1, 2, 3, 4, 5 and 6 during pancreas development by qRT-PCR. To further define the cell-type specificity of the expression of these proteins we use immunofluorescence to co-localize them with Pdx1 at embryonic day 12.5 (E12.5), Ngn3 at E14.5, Pdx1, Nkx2-2, Insulin, Glucagon, Pancreatic polypeptide and Somatostatin at E18.5, as well as Insulin and Glucagon in the adult. We then show that Tle2 can interact with Nkx2-2, Hes1, Arx, and Nkx6-1 which are all critical factors in pancreas development. Finally, we demonstrate that Tle2 modulates the repressive abilities of Arx in a beta-cell line. CONCLUSION: Although Tle1, 2, 3, and 4 show overlapping expression in pancreatic progenitors and in the adult islet, the expression of these factors is restricted to different cell types during endocrine cell maturation. Of note, Tle2 and Tle3 are co-expressed with Gro/TLE interaction domain containing transcription factors that are essential for endocrine pancreas development. We further demonstrate that Tle2 can interact with several of these factors and that Tle2 modulate Arx's repressive activity. Taken together our studies suggest that Gro/TLE proteins play a role in the repression of target genes during endocrine cell specification.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets