Gene regulatory mechanisms connecting metabolism and Alzheimer’s Disease

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By 2050, Alzheimer's disease (AD) will be an epidemic affecting 13.8 million Americans, who will need ongoing medical and social support. There is an urgent need to find mechanisms that can slow or prevent the disease. Metabolism, epigenetics and gene expression have important roles in AD. Metabolic pathways directly regulate biochemical modifications to chromatin at cis-regulatory elements (CREs) that control gene expression. Therefore, specific CREs could be a critical interface between metabolism, gene expression and AD. However, there are millions of CREs in the genome and finding primary CREs for functional studies is a challenge. Our study will define an important new subclass of CRE that affects AD pathology and regulates connections between metabolism, gene expression and AD processes. In unpublished studies, we developed an innovative H3K27ac-targeted paired PLAC-Seq + RNASeq (pPR-Seq) approach to simultaneously profile active CREs, cis-regulatory contacts and gene expression in tissues. For the adult mouse hypothalamus, we uncovered super-looping CREs that form contacts with multiple neighboring genes, and function to coordinate gene co-expression. We call these coordinator CREs (cCREs). We found that cCREs make up 18% of hypothalamic CREs and are significantly enriched at AD risk genes and genes responsive to metabolic changes compared to canonical CREs that regulate single genes. In knockout (KO) mice for one cCRE, we found significant gene expression, metabolic response, behavioral and aging phenotypes. The hypothalamus is an important new area of focus in AD. Others have proposed that early neurodegenerative changes in the hypothalamus contribute to cascading metabolic and homeostatic dysregulation that drives AD progression. Our study builds on this idea with a focus on cCREs. Currently, we do not fully understand the functions of hypothalamic cCREs or how cCREs linked to AD risk genes affect AD brain and behavioral pathology. Moreover, nature of cCREs in the human hypothalamus is unknown. Here, we test the general hypothesis that hypothalamic cCREs are regulatory hubs that disproportionately integrate metabolic and neurodegeneration signals compared to canonical CREs, and regulate the co-expression of neighboring genes, affect the progression AD pathology in mouse models and show conservation between mice and humans. Aim 1 will determine how chromatin accessibility changes at cCREs in response to metabolic and neurodegeneration signals in mice and define the cell-types that different cCREs are active in. Aim 2 will determine the functions of cCREs regulating important AD risk loci, including Abca7, Picalm and Fto-Irx, and effects on AD pathology in 5xFAD mice. Aim 3 will uncover cCREs in the human hypothalamus and determine conservation with mice. In summary, our study will define conserved hypothalamic cCREs that function as important cis-regulatory hubs connecting metabolic and AD processes. By understanding these fundamental new mechanisms that affect primary AD risk genes and processes, future studies will be able to study cCREs in human AD and devise strategies to modify cCRE activity to slow AD progression.