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 In unpublished studies, we developed an innovative H3K27ac-targeted paired PLAC-Seq + RNASeq (pPR-Seq) approach to simultaneously profile active CREs, cis-regulatory contacts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，阿尔茨海默氏病（AD）将成为一种影响1380万美国人的流行病，他们将需要持续 医疗和社会支持。迫切需要寻找可以减慢或预防疾病的机制。 代谢，表观遗传学和基因表达在AD中具有重要作用。代谢途径直接调节 控制基因表达的顺式调节元件（CRE）对染色质的生化修饰。 因此，特定的CRE可能是代谢，基因表达和AD之间的关键接口。然而， 基因组中有数百万个渐进液，找到用于功能研究的主要CRE是一个挑战。我们的 研究将定义一个重要的CRE新子类，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靶向配对的Plac-Seq + RNASEQ（PPR-SEQ）方法 同时介绍了组织中的活性CRE，顺式调节触点和基因表达。对于成年人 小鼠下丘脑，我们发现了与多个相邻基因接触的超浮动板 和函数以协调基因共表达。我们称这些协调员CRE（CCRES）。我们发现 CCR占下丘脑CRE的18％，并在AD风险基因和基因上显着富集 与调节单个基因的规范CRE相比，对代谢变化的反应敏感。在淘汰赛（KO）中 一个CCRE的小鼠，我们发现了明显的基因表达，代谢反应，行为和衰老 表型。下丘脑是AD中重点的重要新领域。其他人提出了早期 下丘脑的神经退行性变化有助于级联代谢和稳态 驱动AD进展的失调。我们的研究以这个想法为基础，重点是CCR。目前，我们 不要完全了解下丘脑CCR的功能或与AD风险基因相关的CCR如何影响AD 大脑和行为病理学。而且，人类下丘脑中CCR的性质尚不清楚。在这里，我们 测试一般假设，即下丘脑CCR是不成比例整合的调节枢纽 与规范CRE相比，代谢和神经变性信号，并调节 相邻基因，影响小鼠模型中的进展AD病理，并显示 老鼠和人类。 AIM 1将确定染色质的可及性如何响应于CCRS 小鼠中的代谢和神经变性信号，并定义不同CCR活性的细胞类型。 AIM 2将确定调节重要AD风险基因座的CCR的功能，包括ABCA7，PICALM和 FTO-IRX，以及对5XFAD小鼠AD病理学的影响。 AIM 3将在人类下丘脑中发现CCR 并确定小鼠的保护。总而言之，我们的研究将定义保守的下丘脑CCRES 功能与连接代谢过程和AD过程的重要顺式调节枢纽。通过理解这些 基本的新机制影响主要的AD风险基因和过程，未来的研究将能够 研究人类AD中的CCR，并制定了修改CCRE活性以减慢AD进展的策略。