神经限制性沉默因子REST对逆转录转座子LINE-1转座的表观遗传学调控

Retrotransposon LINE-1 is major driving force in genome evolution. As reported, the transposition and insertion of LINE-1 could potentially cause various diseases including cancers and its methylation status has been actively investigated as a diagnostic and prodiagonistic biomarker. Despite the scientific and clinical significance of LINE-1 research our knowledge of the mechanisms controlling LINE-1 transposition and methylation remains very limited. REST is a master transcription repressor and epigenetic factor capable to modulate the expression of thousands of genes and crucial in many physiological and pathological processes. We have recently made a conditional REST knockout mouse allelle and uncovered a key role of REST in epigenetic control of adult neural stem cell fates and the progression of neurogenesis. Importantly consistent with an earlier bioinformatic studies, our preliminary results suggest LINE-1 could potentially be REST target genes. In this proposed study, we will utilize the conditional REST knockout allele and robust quiescent neural stem cell culture systems we have developed. We aim to elucidate the epigenetic mechanisms of REST and its corepressor complexes in modulating the dynamic expression, transposition and methylation of LINE-1 in neural regeneratin and neural cells. For pathological conditions, we choose to dissect the epigenetics underlying how HDAC inhibitors(VPA/TSA) and REST control the activity of LINE-1 both in established tumor cell lines and in primary cancer cells. This proposed study has the potential to shed much needed light on the epigenetic control of LINE-1 activity and to elucidate how LINE-1 and REST may be implicated in relevant pathogenesis and/or therapy. Eventually we hope that our studies can provide novel insights and thinking in disease diagonistics and treatments.

逆转录转座子LINE-1是介导基因组进化的主要动力，转座引起的突变能导致癌症等疾病，而其甲基化状态正成为疾病诊断和疗效的生物标记物。虽然LINE-1研究的科学和临床意义重大，但我们对其调控机制知之甚少。REST是重要的转录和表观遗传分子，影响数千个基因的表达，已有数据提示LINE-1及相关转座子序列是潜在的REST靶基因。结合神经干细胞静息培养体系和条件性REST基因敲除小鼠模型，我们希望解析在神经再生和神经细胞中REST及其抑制复合体对LINE-1表达、转座和甲基化动态的表观遗传调控。在癌组织和细胞系中阐明HDAC抑制剂（VPA/TSA）和REST对LINE-1及相关序列的调控。结合多学科方法学和技术体系，本研究将为神经相关疾病和癌症中LINE-1的调控提供可能的机理，并提示LINE-1和REST在疾病发生和治疗中的可能机制，为诊断治疗提供新的理论基础和策略。