Bec1/CtBP1複合體在神經分化及漢丁頓舞蹈症對含有RE1/NRSE 基因表現的調控

Abstract

漢丁頓舞蹈症是一種遺傳性的神經退化性疾病，主要的特徵是由REST/NRSF所調控的基因轉錄受到抑制，導致紋狀體的神經細胞大量死亡。REST/NRSF是一個抑制型轉錄因子，會與啟動子上一段含有23個鹼基對的保守序列RE1/NRSE結合，藉此在胚胎幹細胞、未分化的神經先驅幹細胞及非神經細胞中，抑制與許多神經有關的基因表現。REST/NRSF會招募許多輔助抑制物，包括C端結合蛋白CtBP1， 而形成一個新奇複合物，藉此執行抑制的功能。我們實驗室先前從GCH-1的顯性負面調控機制中，鑑定了一個新奇基因Bec1。Bec1的C端有一個保守的YTH區域，此保守區域曾被證明具有與RNA結合及ATP水解酶的能力。在我們的研究中，我們發現Bec1會藉由與CtBP1結合，來誘導某些含有RE1/NRSE序列的基因表現，例如：SCG10、BDNF。同時，Bec1的YTH區域對於Bec1及CtBP1兩者間結合是很重要的。另外，我們實驗室之前的實驗結果顯示Bec1在R6/2老鼠中，其表現量會降低，而我們的實驗結果也發現突變的Huntingtin會減少細胞中可溶解的Bec1蛋白質。Bec1蛋白質表現量的降低可能也是造成在漢丁頓舞蹈症中含有RE1/NRSE序列的基因表現受到抑制的原因之一。

Huntington’s disease is an inherited neurodegenerative disease characterized by the repression of REST/NRSF target gene transcription, leading to large amounts of neuron death in the striatum. REST/NRSF is a silencing transcription factor binding to a consensus 23bp DNA sequence in promoter, RE1/NRSE, to restrict neural gene expression in embryo stem cells, undifferentiated neuronal progenitor and non-neuronal cells. REST/NRSF recruits a lot of corepressor, including a C-terminal binding protein, CtBP1, and forms a novel corepressor complex, to exert repression activity. Our lab previously identified a novel gene, Bec1, from the GCH-1 dominant negative cell models. The C-terminal of Bec1, a conserved YTH domain, has been recorded having RNA-binding and ATPase ability. In our study, we discovered that Bec1 can induce some RE1/NRSE-containing gene expression, such as SCG10 and BDNF, through interaction with CtBP1. Meanwhile, the YTH domain of Bec1 is important for Bec1 and CtBP1 interaction. Furthermore, our lab previously shows that Bec1 is reduced in R6/2 mice and our data also are found that mutant Htt reduces soluble Bec1 in cells. The reduction of Bec1 might be a reason for RE1/NRSE gene repression in HD.