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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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title proceedings of the national academy of sciences of the united states of america
Publication Year Start




PMID- 16651517
OWN - NLM
STAT- MEDLINE
DCOM- 20060719
LR  - 20171116
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 19
DP  - 2006 May 9
TI  - Groucho/transducin-like Enhancer-of-split (TLE)-dependent and -independent
      transcriptional regulation by Runx3.
PG  - 7384-9
AB  - 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.
FAU - Yarmus, Merav
AU  - Yarmus M
AD  - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100,
      Israel.
FAU - Woolf, Eilon
AU  - Woolf E
FAU - Bernstein, Yael
AU  - Bernstein Y
FAU - Fainaru, Ofer
AU  - Fainaru O
FAU - Negreanu, Varda
AU  - Negreanu V
FAU - Levanon, Ditsa
AU  - Levanon D
FAU - Groner, Yoram
AU  - Groner Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060501
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antigens, CD)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (CD4 Antigens)
RN  - 0 (Core Binding Factor Alpha 3 Subunit)
RN  - 0 (Integrin alpha Chains)
RN  - 0 (Repressor Proteins)
RN  - 0 (Runx3 protein, mouse)
RN  - 0 (alpha E integrins)
RN  - 0 (groucho protein, Drosophila)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antigens, CD/metabolism
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism
MH  - CD4 Antigens/metabolism
MH  - CD8-Positive T-Lymphocytes/metabolism
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Cercopithecus aethiops
MH  - Core Binding Factor Alpha 3 Subunit/chemistry/genetics/*metabolism
MH  - Dendritic Cells/cytology/metabolism
MH  - Down-Regulation
MH  - Enhancer Elements, Genetic
MH  - Gene Expression Regulation
MH  - Humans
MH  - Integrin alpha Chains/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Phenotype
MH  - Repressor Proteins/genetics/*metabolism
MH  - Transcription, Genetic/genetics
PMC - PMC1464349
EDAT- 2006/05/03 09:00
MHDA- 2006/07/20 09:00
CRDT- 2006/05/03 09:00
PHST- 2006/05/03 09:00 [pubmed]
PHST- 2006/07/20 09:00 [medline]
PHST- 2006/05/03 09:00 [entrez]
AID - 0602470103 [pii]
AID - 10.1073/pnas.0602470103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 May 9;103(19):7384-9. doi:
      10.1073/pnas.0602470103. Epub 2006 May 1.