Comparative DNA methylomic analyses reveal potential origins of novel epigenetic biomarkers of insulin resistance in monocytes from virally suppressed HIV-infected adults

Clinical Epigenetics

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[1] 0000 0001 2188 0957, grid.410445.0, Department of Native Hawaiian Health, University of Hawaii John A. Burns School of Medicine, 677 Ala Moana Blvd, Suite 1016B, University of Hawaii, 96813, Honolulu, HI, USA;0000 0001 2188 0957, grid.410445.0, Department of Tropical Medicine, University of Hawaii, 651 Illalo Street, BSB 325C, 96815, Honolulu, HI, USA;0000 0001 2188 0957, grid.410445.0, Department of Molecular Bioscience and Bioengineering, University of Hawaii, 1955 East-West Road, Ag. Science 208, 96822, Honolulu, HI, USA;0000 0001 2188 0957, grid.410445.0, Hawaii Center for AIDS, University of Hawaii, 651 Ilalo St. BSB 231, 96813, Honolulu, HI, USA;0000 0001 2188 0957, grid.410445.0, Office of Biostatistics & Quantitative Health Sciences, University of Hawaii John A. Burns School of Medicine, 651 Ilalo Street, Medical Education Building, Suite 411, 96813, Honolulu, HI, USA;0000 0004 1936 9166, grid.412750.5, School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Ave., CU430708, 14642, Rochester, NY, USA;

关键词: Monocyte;    Insulin resistance;    Diabetes;    DNA methylation;    Epigenetics;    Inflammation;    Immune response;    Cardiometabolic disease;    HIV;   

DOI  :  10.1186/s13148-019-0694-1

来源: publisher

【 摘 要 】

BackgroundCompared to healthy individuals, those with stably repressed HIV experience a higher risk of developing insulin resistance, a hallmark of pre-diabetes and a major determinant for cardiometabolic diseases. Although epigenetic processes, including in particular DNA methylation, appear to be dysregulated in individuals with insulin resistance, little is known about where these occur in the genomes of immune cells and the origins of these alterations in HIV-infected individuals. Here, we examined the genome-wide DNA methylation states of monocytes in HIV-infected individuals (n = 37) with varying levels of insulin sensitivity measured by the homeostatic model assessment of insulin resistance (HOMA-IR).ResultsBy profiling DNA methylation at single-nucleotide resolution using the Illumina Infinium HumanMethylation450 BeadChip in monocytes from insulin-resistant (IR; HOMA-IR ≥ 2.0; n = 14) and insulin-sensitive (IS; HOMA-IR < 2.0; n = 23) individuals, we identified 123 CpGs with significantly different DNA methylation levels. These CpGs were enriched at genes involved in pathways relating to glucose metabolism, immune activation, and insulin-relevant signaling, with the majority (86.2%) being hypomethylated in IR relative to IS individuals. Using a stepwise multiple logistic regression analysis, we observed 4 CpGs (cg27655935, cg02000426, cg10184328, and cg23085143) whose methylation levels independently predicted the insulin-resistant state at a higher confidence than that of clinical risk factors typically associated with insulin resistance (i.e., fasting glucose, 120-min oral glucose tolerance test, Framingham Risk Score, and Total to HDL cholesterol ratio). Interestingly, 79 of the 123 CpGs (64%) exhibited remarkably similar levels of methylation as that of hematopoietic stem cells (HSC) in monocytes from IR individuals, implicating epigenetic defects in myeloid differentiation as a possible origin for the methylation landscape underlying the insulin resistance phenotype. In support of this, gene ontology analysis of these 79 CpGs revealed overrepresentation of these CpGs at genes relevant to HSC function, including involvement in stem cell pluripotency, differentiation, and Wnt signaling pathways.ConclusionAltogether, our data suggests a possible role for DNA methylation in regulating monocyte activity that may associate with the insulin-resistant phenotype. The methylomic landscape of insulin resistance in monocytes could originate from epigenetic dysregulation during HSC differentiation through the myeloid lineage. Understanding the factors involved with changes in the myeloid trajectory may provide further insight into the development of insulin resistance. Furthermore, regulation of specific genes that were implicated in our analysis reveal possible targets for modulating immune activity to ameliorate insulin resistance.

【 授权许可】

CC BY