Chromatin Signaling Mechanisms in Metabolic Aging and Disease

Our broad research goal is to understand chromatin regulatory mechanisms in nuclear and epigenetic programs and how these mechanisms are deregulated in aging and disease. A fundamental mechanism for regulating chromatin involves the reversible modification of histones by chemical moieties such as acetyl-, methyl-, and phospho- groups. These different histone marks are linked to discrete chromatin states and regulate the accessibility of DNA to transacting factors. In budding yeast, histone deacetylation by the chromatin silencing factor Sir2 prevents genomic instability and aging, and in mammals, de-regulation of histone acetylation is linked to cellular senescence and aging-related pathologies from neurodegeneration to cancer. Here, we focus on the mammalian Sir2 family member SIRT7, a chromatin regulatory, highly selective, lysine deacetylase enzyme. Previous studies reported that loss of SIRT7 function in mice leads to genomic instability, shortened lifespan and aging-related phenotypes including fatty liver, cardiac disease, and hematopoietic stem cell dysfunction. This project will study new roles of SIRT7-dependent histone deacetylation in chromatin regulatory mechanisms that are deregulated in aging-associated metabolic pathologies. It employs biochemical, cellular, and genomic approaches, and leverages SIRT7 knockout (SIRT7-KO) mice and new mouse models in which SIRT7 is overexpressed (SIRT7-OE). A central hypothesis is that SIRT7 protects against aging and metabolic disease processes and attenuates metabolic pathologies when overexpressed in mice. The project also hypothesizes that a novel histone substrate of SIRT7, H3K36, contributes to functions of SIRT7 in aging and metabolic pathways. Little is known about acetylation of H3K36, but di-methylation of H3K36 (a histone modification linked to gene regulation) is implicated in many human cancers, developmental disorders, and recently, metabolic disease. We hypothesize that deacetylation of H3K36 by SIRT7 is coupled to methylation by lysine methyltransferase (KMT) enzymes. We will test the model that a key mechanistic function of SIRT7 is to clear H3K36 acetylation from large swaths of DNA across the genome to enable methylation by KMTs, and that such a H3K36 acetyl-methyl switch mechanism is essential for preventing aging-associated gene expression reprograming in metabolic tissues. Project Number: 1R01AG093112-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Katrin Chua | Institution: PALO ALTO VETERANS INSTIT FOR RESEARCH, PALO ALTO, CA | Award Amount: $542,730 | Activity Code: R01 | Study Section: Cellular Mechanisms in Aging and Development Study Section[CMAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11109241