Gene regulatory mechanisms connecting metabolism and Alzheimer’s Disease

连接新陈代谢和阿尔茨海默病的基因调控机制

• 批准号: 10660149
• 负责人: Chris Gregg
• 金额: $ 230.73万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660149
• 关键词: ATAC-seq; Accidents; Adult; Affect; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Apolipoprotein E; Area; Behavior; Behavioral; Biochemical; Brain; Cell Nucleus; Cessation of life; ChIP-seq; Chromatin; Chromium; Disease; Disease Progression; Epidemic; Epigenetic Process; Fasting; Female; Foundations; Future; Gene Cluster; Gene Expression; Genes; Genetic; Genome; Gliosis; Goals; Human; Human Biology; Hypothalamic structure; In Situ Hybridization; Inflammation; Knock-out; Knockout Mice; Ligation; Link; Medical; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Modeling; Modification; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Pathology; Phenotype; Process; Public Health; RNA; Regulator Genes; Regulatory Element; Research; Role; Senile Plaques; Signal Transduction; Sleep; Social support; Stress; Symptoms; Testing; Therapeutic; Tissues; blood glucose regulation; cell type; chromatin immunoprecipitation; disorder control; feeding; improved; innovation; male; mouse model; multiple omics; neuron loss; novel; prevent; response; risk variant; single-cell RNA sequencing; transcriptome sequencing

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 In unpublished studies, we developed an innovative H3K27ac-targeted paired PLAC-Seq + RNASeq (pPR-Seq) approach to simultaneously profile active CREs, cis-regulatory contacts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.

到 2050 年，阿尔茨海默病 (AD) 将成为一种影响 1,380 万美国人的流行病，他们需要持续的治疗 医疗和社会支持。迫切需要找到可以减缓或预防该疾病的机制。 代谢、表观遗传学和基因表达在 AD 中发挥着重要作用。代谢途径直接调节 控制基因表达的顺式调控元件 (CRE) 处染色质的生化修饰。 因此，特定的 CRE 可能是代谢、基因表达和 AD 之间的关键界面。然而， 基因组中有数百万个 CRE，寻找用于功能研究的主要 CRE 是一项挑战。我们的 研究将定义 CRE 的一个重要的新亚类，它影响 AD 病理并调节 新陈代谢、基因表达和 AD 过程之间的联系。在未发表的研究中，我们 开发了一种创新的 H3K27ac 靶向配对 PLAC-Seq + RNASeq (pPR-Seq) 方法 同时分析组织中的活性 CRE、顺式调控接触和基因表达。对于成人 小鼠下丘脑，我们发现了与多个邻近基因形成接触的超级循环 CRE， 和协调基因共表达的功能。我们将这些协调器 CRE (cCRE) 称为协调器 CRE。我们发现 cCRE 占下丘脑 CRE 的 18%，并且 AD 风险基因和基因显着富集 与调节单基因的典型 CRE 相比，它对代谢变化敏感。淘汰赛（KO） 对于一种 cCRE 的小鼠，我们发现显着的基因表达、代谢反应、行为和衰老 表型。下丘脑是 AD 的一个重要的新焦点区域。还有人建议尽早 下丘脑的神经退行性变化有助于级联代谢和稳态 导致 AD 进展的失调。我们的研究建立在这个想法的基础上，重点关注 cCRE。目前，我们 不完全了解下丘脑 cCRE 的功能或与 AD 风险基因相关的 cCRE 如何影响 AD 大脑和行为病理学。此外，人类下丘脑中 cCRE 的性质尚不清楚。在这里，我们 检验下丘脑 cCRE 是不成比例整合的调节中心的一般假设 与典型的 CRE 相比，代谢和神经退行性信号，并调节共表达 邻近基因，影响小鼠模型中 AD 病理学的进展，并显示出之间的保守性 老鼠和人类。目标 1 将确定 cCRE 的染色质可及性如何变化以响应 小鼠体内的代谢和神经变性信号，并定义不同 cCRE 活跃的细胞类型。 目标 2 将确定 cCRE 调节重要 AD 风险位点的功能，包括 Abca7、Picalm 和 Fto-Irx 以及对 5xFAD 小鼠 AD 病理学的影响。目标 3 将揭示人类下丘脑中的 cCRE 并用小鼠确定保守性。总之，我们的研究将定义保守的下丘脑 cCRE， 作为连接代谢和 AD 过程的重要顺式调节中心。通过了解这些 影响主要 AD 风险基因和过程的基本新机制，未来的研究将能够 研究人类 AD 中的 cCRE 并制定策略来修改 cCRE 活性以减缓 AD 进展。