Higher Order Chromatin and Genetic Risk for Alzheimer's Disease

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

PROJECT SUMMARY The genetics of Alzheimer's Dementia (AD) is advancing at rapid pace. An increasing number of risk- associated polymorphisms and variants are found in intergenic, intronic and other non-coding sequence. However, it has been a major challenge to design testable hypotheses to elucidate the potential function of such types of disease-associated non-coding DNA. Many of these sequences are thought to exert regulatory functions, including longe range enhancer elements physically interacting with transcription start sites (TSS) separated on the linear genome by many kilobases of interspersed DNA. We have generated a comprehensive annotation map of open chromatin and enhancer sequences in tissue and cellular populations that are relevant to the pathophysiology of AD. By applying a high-resolution expression quantitative trait loci (eQTL) map, we have identified AD associated noncoding regions that are positioned within regulatory regions tagged with combinatorial histone modification signatures indicative of active enhancers (AD-Associated Enhancers or ADAEs). ADAEs are strong candidates for future validation studies using approaches such as epigenomic editing in iPSC-derived cells. Because, these functional validation studies require substantial funds and are time consuming, it is critical to target ADAEs with validated enhancer function. The overall objective of this supplement is to optimize transgenic expression vectors and confirm enhancer status via mouse transgenesis for the 5 top ADAEs. Following confirmation of accurate enhancer activity, mice from specific lines will be examined at different ages. The multidimensional approach presented here provides a roadmap to unravel the neurological functions of the largely unexplored non-coding sequences of the human genome in brain tissue.