Interactions among insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts
Nida Haider, C. Ronald Kahn
Nida Haider, C. Ronald Kahn
Published November 30, 2023
Citation Information: J Clin Invest. 2024;134(2):e172333. https://doi.org/10.1172/JCI172333.
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Research Article Cell biology Metabolism

Interactions among insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts

Abstract

About 25% of people in the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of induced pluripotent stem cells differentiated into myoblasts (iMyos) from insulin-resistant (I-Res) versus insulin-sensitive (I-Sen) nondiabetic individuals revealed that 306 genes increased and 271 genes decreased in expression in iMyos from I-Res donors with differences of 2-fold or more. Over 30 of the genes changed in I-Res iMyos were associated with T2D by SNPs and were functionally linked to insulin action and control of metabolism. Interestingly, we also identified more than 1,500 differences in gene expression that were dependent on the sex of the cell donor, some of which modified the insulin resistance effects. Many of these sex differences were associated with increased DNA methylation in cells from female donors and were reversed by 5-azacytidine. By contrast, the insulin sensitivity differences were not reversed and thus appear to reflect genetic or methylation-independent epigenetic effects.

Authors

Nida Haider, C. Ronald Kahn

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Figure 4

Autosomal sex-specific gene expression changes are independent of X chromosome dosage and androgen receptor action.

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Autosomal sex-specific gene expression changes are independent of X chro...
(A) mRNA expression level of XIST in I-Sen and I-Res iMyos from male and female donors showing 2 subgroups based on XIST expression level, XIST high and XIST low, in female individuals. (B) PCA plot of only the genes present on the autosomal chromosomes showing changes based on sex (blue, males; green, XIST low females; red, XIST high females) and insulin sensitivity status (open shapes, I-Sen; filled shapes, I-Res). (C) Schematic overview of the data analysis comparing male individuals with XIST low and -high female individuals. (D) Pie graphs showing the distribution of the male-dominant genes (n = 1,840, P < 0.05) and female-dominant genes (n = 1,607, P < 0.05) based on X dose and/or XIST level dependency. (E) mRNA levels of AR in I-Sen and I-Res iMyos from male and female donors from RNA-Seq data. Data are shown as the mean ± SEM, n = 4 per group. **P < 0.01 I-Sen vs. I-Res in males, or ##P < 0.01, ###P < 0.001 I-Sen males vs. I-Sen, I-Res females, 1-way ANOVA followed by correction for multiple comparison by controlling the FDR. (F) mRNA levels of AR relative to β-actin in I-Sen and I-Res iMyos from male donors upon treatment with 10 μM DHT for 4 days. Data are shown as the mean ± SEM, n = 4 per group. (G) 2-NBDG glucose uptake assay in male iMyos stimulated with 100 nM of insulin for 30 minutes following pretreatment with 10 μM DHT for 4 days. Data are shown as the mean ± SEM, n = 4 per group. *P < 0.05, **P < 0.01, ***P < 0.001 basal vs. insulin; ##P < 0.01, ####P < 0.0001 I-Sen control vs. I-Sen DHT (basal and insulin); and ###P < 0.001 I-Res control vs. I-Res DHT (insulin); 2-way ANOVA followed by correction for multiple comparison by controlling the FDR.