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.
Our proposed research aims to forge a new path in ?translational epigenetics? where an entire chromosome, and potentially a small region or locus, is silenced by a novel RNA. This work will accelerate basic and translational research for Down syndrome and will pursue the novel concept of ?chromosome therapy? which we propose to investigate in vitro and in vivo. In addition to relevance for Down syndrome, our aims have potentially broad relevance for other conditions, including Alzheimer's disease and a variety of duplication disorders. This work will also advance basic understanding of RNA regulation and epigenetic plasticity of the genome.
