Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome

摘要 这项研究的更广泛的愿景是开发“翻译表观遗传学”这一基本未被开发的潜力。 对XIST RNA的研究和对唐氏综合症的进一步了解和潜在的治疗策略。人类 Xist/小鼠Xist编码一种独特的长非编码RNA，具有诱导稳定的能力 表观遗传沉默，在顺式。而XIST RNA和X染色体剂量补偿的基本生物学是 经过认真研究，我们的实验室正在努力开拓XIST剂量补偿的翻译潜力 常见的染色体失衡，尤其是唐氏综合症。染色体异常仍然是一种主要的， 人类遗传负担中未解决的一部分，发生在140个新生儿中。这将是“改变游戏规则的”，如果 携带21三体的细胞中数百个基因的过度表达可以通过操纵Just来解决 一个基因，XIST。劳伦斯实验室最近在体外证明了一个大的XIST基因可以准确地 插入到一条21号染色体上，并诱导出人意料的全面、稳定的三体沉默 常染色体，显示于来源于DS患者细胞的未分化的iPS细胞。我们现在正在寻求资金，以期在此基础上 为追求下一个雄心勃勃的目标而最近取得进展的坚实基础；测试和发展较长期的 体内三体沉默的潜在研究进展。为此，我们将调查XIST中介的 人类大脑中的染色体沉默及其逆转或减轻细胞或机体病理的能力 器官和神经细胞，并在一个研究得很好的DS三体小鼠模型中。除了与DS相关之外， 我们的研究与阿尔茨海默病直接相关，阿尔茨海默病几乎不可避免地会在20-30年内发生 唐氏综合症患者。通过将我们的一些目标集中在应用程序位置，我们将测试以下策略 APP的靶基因治疗是插入XIST转基因进行染色体治疗的第一步。我们有 组建了一个由联合调查员和合作者组成的多学科团队，由两名个人助理领导，并相互补充 专业知识，我们将一起测试策略并探索XIST RNA提供的多功能 唐氏综合症和其他潜在疾病的“翻译表观遗传学”工具。

ABSTRACT The broader vision of this research is to develop the largely unexplored potential for “translational epigenetics” of XIST RNA and advance understanding and a potential therapeutic strategy for Down Syndrome. Human XIST/mouse Xist encodes a unique long non-coding RNA with the well-established power to induce stable epigenetic silencing, in cis. While the basic biology of XIST RNA and X-chromosome dosage compensation is heavily studied, our lab is working to pioneer the translational potential of XIST dosage compensation for common chromosomal imbalances, particularly Down Syndrome. Chromosomal abnormalities remain a major, unaddressed part of the human genetic burden, occurring in 1/140 births. It would be “game-changing” if the over-expression of hundreds of genes in cells carrying trisomy 21 could be addressed by manipulation of just one gene, XIST. The Lawrence lab recently demonstrated in vitro that a large XIST cDNA could be accurately inserted into one chromosome 21 and induce surprisingly comprehensive, stable “trisomy silencing” of the autosome, shown in undifferentiated iPS cells derived from DS patient cells. We now seek funding to build on a strong foundation of recent progress in pursuit of the next ambitious goal; to test and develop the longer-term potential development for trisomy silencing in vivo. To this end, we will investigate XIST-mediated chromosomal silencing and its ability to reverse or mitigate cell or organism pathology, in human cerebral organoid and neural cells and in a well-studied trisomic mouse model of DS. In addition to relevance for DS, our studies have direct relevance for Alzheimer Disease, which occurs almost inevitably and 20-30 years in individuals with Down Syndrome. By focusing some of our goals on the APP locus, we will test strategies that target gene therapy for APP as a first step to insertion of XIST transgenes for chromosome therapy. We have assembled a multi-disciplinary team of co-investigators and collaborators, led by two PIs with complementary expertise, and together we will test strategies and probe the full potential that XIST RNA provides a versatile tool for “translational epigenetics” for Down Syndrome and potentially other conditions.