PDF(Pubmed)
Abstract：
T-box transcription factor 20 (Tbx20) plays a multifaceted role in cardiac morphogenesis and controls a broad gene regulatory network. However, the mechanism by which Tbx20 activates and represses target genes in a tissue-specific and temporal manner remains unclear. Studies show that Tbx20 directly interacts with the Transducin-like Enhancer of Split (TLE) family of proteins to mediate transcriptional repression. However, a function for the Tbx20-TLE transcriptional repression complex during heart development has yet to be established. We created a mouse model with a two amino acid substitution in the Tbx20 EH1 domain, thereby disrupting the Tbx20-TLE interaction. Disruption of this interaction impaired crucial morphogenic events, including cardiac looping and chamber formation. Transcriptional profiling of Tbx20EH1Mut hearts and analysis of putative direct targets revealed misexpression of the retinoic acid pathway and cardiac progenitor genes. Further, we show that altered cardiac progenitor development and function contribute to the severe cardiac defects in our model. Our studies indicate that TLE-mediated repression is a primary mechanism by which Tbx20 controls gene expression.
摘要：
T-box转录因子20（Tbx20）在心脏形态发生中起着多方面的作用，并控制着广泛的基因调控网络。然而,Tbx20以组织特异性和时间方式激活和抑制靶基因的机制尚不清楚.研究表明，Tbx20直接与Transducin样分裂增强子（TLE）蛋白家族相互作用以介导转录抑制。然而,Tbx20-TLE转录抑制复合物在心脏发育过程中的功能尚未建立。我们创建了一个在Tbx20EH1域中具有两个氨基酸取代的小鼠模型,从而破坏Tbx20-TLE相互作用。这种相互作用的破坏损害了关键的形态发生事件，包括心脏循环和腔室形成。Tbx20EH1Mut心脏的转录分析和推定的直接靶标的分析揭示了视黄酸途径和心脏祖细胞基因的错误表达。Further,在我们的模型中,我们发现心脏祖细胞发育和功能的改变导致了严重的心脏缺陷.我们的研究表明，TLE介导的抑制是Tbx20控制基因表达的主要机制。
