213-OR: Widespread Age-Associated Changes in the Chromatin Architecture of Skeletal Muscle Cell Types

Introduction & Objective: Genome-wide association studies (GWAS) have found >1,000 signals associated with type 2 diabetes (T2D), most of which occur in noncoding genomic regions. T2D risk increases with age, and aging is accompanied by changes in the epigenomic landscape. Together, these findings suggest that age-related epigenomic change may contribute to T2D risk. Here we profile age-associated epigenomic changes in skeletal muscle, a T2D relevant tissue.

Methods: We analyzed single nucleus ATAC-seq data from 284 Finnish skeletal muscle biopsies (donor age 20-79 years; mean = 60) to identify age-associated patterns in chromatin accessibility. We used Type 1, 2a, and 2x muscle fiber, endothelial, and fibro/adipogenic progenitor nuclei for analysis. To find age-associated open chromatin regions (OCRs) without assuming linearity, we used Auto-Regressive Integrated Moving Average (ARIMA) models. We then characterized these OCRs with k-means clustering as well as logistic and linkage disequilibrium score (ldsc) regression enrichment tests.

Results: Across cell types 6.2 - 15.5% of tested OCRs were age-associated (11,925 - 23,143 OCRs). These OCRs clustered into four patterns of age association: linear positive (Up)/negative (Down) and parabolic positive (Valley)/negative (Arch). These patterns showed distinct enrichment in both gene sets, such as the fast to slow fiber transition gene set in arch patterned Type 1 OCRs (FDR = 2x10^-6), and chromatin states, such as active enhancer chromatin in down patterned Type 2a OCRs (nominal p = 2x10^-29). Ldsc analysis found T2D GWAS signal enrichment in Type 2a up patterned OCRs (nominal p = 0.03). Additionally, 12 age-associated OCRs are chromatin accessibility quantitative trait loci that colocalize with T2D GWAS signals.

Conclusion: These results highlight age-associated epigenomic changes and enrichment for T2D GWAS signals in skeletal muscle cell types, providing a basis for research into development and aging in a T2D relevant tissue.