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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Groucho/transducin-like Enhancer-of-split (TLE)-dependent and -independent transcriptional regulation by Runx3
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Groucho/transducin-like Enhancer-of-split (TLE)-dependent and -independent transcriptional regulation by Runx3

机译：Groucho /转导蛋白样分裂增强子（TLE）依赖和独立的Runx3转录调控

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摘要

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 (TILE). 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 alpha E/CD103-like WT Runx3, whereas unlike wild type, it failed to repress alpha E/CD103 in CD8(+) splenocytes. Thus, in CD8-lineage T cells, Runx3 regulates alpha E/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 panCD8(+) 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.
机译：组织特异性转录因子对基因表达的调控涉及开启和关闭靶基因的转录。 Runx3是一种矮小域转录因子，它通过激活和抑制感觉神经元，树突状细胞（DC）和T细胞中的基因表达来调节细胞内在功能。为了在体内研究Runx3介导的阻遏机制，我们生成了表达缺乏C末端VWRPY突变Runx3的小鼠，Runx3是Runx3与核心加压因子Groucho / transducin-like splitter（TILE）相互作用所需的基序）。与Runx3（-/-）小鼠由于背根神经节TrkC神经元死亡而表现出共济失调相反，Runx3（VWRPY-/-）小鼠没有共济失调，具有完整的背根神经节神经元，表明Runx3的能力系绳Groucho / TLE对神经发生不是必需的。在DC区室中，突变蛋白Runx3（VWRPY-）促进了正常发育的皮肤Langerhans细胞，但未能抑制DC自发成熟，表明该后期过程涉及Runx3介导的通过Groucho / TLE募集的抑制。此外，在CD8（+）胸腺细胞中，Runx3（VWRPY-）上调alpha E / CD103样的WT Runx3，而与野生型不同，它无法抑制CD8（+）脾细胞中的alpha E / CD103。因此，在CD8系T细胞中，Runx3以相反的调控模式调控αE / CD103，并募集Groucho / TLE来促进从激活到抑制的转变。 Runx3（VWRPY-）也未能介导CD8 + T细胞中CD4基因的表观遗传沉默，但通常调节其他panCD8（+）T细胞基因。这些数据提供了Groucho / TLE对Runx3介导的CD4沉默的要求，并与其他Runx3调控基因在表观遗传上沉默的机制有关。

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