Insulin Resistance in Women Correlates with Chromatin Histone Lysine Acetylation, Inflammatory Signaling, and Accelerated Aging

Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a bro...

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Bibliographic Details
Published in:	Cancers Vol. 16; no. 15; p. 2735
Main Authors:	Vidal, Christina M, Alva-Ornelas, Jackelyn A, Chen, Nancy Zhuo, Senapati, Parijat, Tomsic, Jerneja, Robles, Vanessa Myriam, Resto, Cristal, Sanchez, Nancy, Sanchez, Angelica, Hyslop, Terry, Emwas, Nour, Aljaber, Dana, Bachelder, Nick, Martinez, Ernest, Ann, David, Jones, Veronica, Winn, Robert A, Miele, Lucio, Ochoa, Augusto C, Dietze, Eric C, Natarajan, Rama, Schones, Dustin, Seewaldt, Victoria L
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-08-2024
Subjects:	Acetylation Aging Analysis Breast cancer Cancer Cardiovascular diseases Chromatin Cytokines Development and progression Diabetes Diabetes mellitus Disease resistance DNA damage DNA methylation Environmental changes Environmental factors Epigenetic inheritance Epigenetics Ethylenediaminetetraacetic acid Flow cytometry Genes Genomes Glucose Health aspects Heart diseases Histones Human subjects Hyperinsulinemia Inflammation Innate immunity Insulin resistance Kidney diseases Lymphocytes T Lysine Medical records Metabolism Metabolites Methylation NF-κB protein Oncology, Experimental Plasma Prediabetic state Review boards Senescence T cells Tumor necrosis factor-α Type 2 diabetes Women Womens health United States > US senescence chromatin acetylation TNF-alpha histone H3K9ac tissue inflammation interlukin-6 (IL6) SASP insulin resistance epigenetics
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Summary:	Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top "hit" was chromatin opening at H3K9ac. Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2072-6694 2072-6694
DOI:	10.3390/cancers16152735