Fig. 7. Progression of T1D pathogenesis correlates with ER-stress-induced adaptive exhaustion and suppression of β-cell maturity markers.

a Schematic representation of the common genes between the β-cell specific adaptome in MIN6 cells (78 genes) and the β-cells scRNA-seq datasets. Plots show the regulation of the 46 genes in MIN6 cells during acute and chronic ER stress (middle) and β-cells scRNA-seq from healthy and T1D patients (right). b Relevant distance in gene expression between two data sets: (tSNE1) scRNA-seq dataset from all human β-cells (healthy and T1D, 8349) and (tSNE2) the expression of a group of genes consisting of both, the UPR signature genes (GO:0030968), and 6 β-cell-specific gene markers (INS, PAX6, NKX2.2, NKX6.1, MAFA and PDX1). Colored from left to right, T1D progression, INS, BiP and WFS1. Darker color indicates higher expression of the respective genes. Raw data were normalized as described in Materials and Methods. c pseudotime analaysis of tSNE data from b, showing decrease in β-cell markers and increase in BiP. d Schematic of stress/recovery cycles and Western blot analysis of UPR and β-cell identity genes. e Western blot analysis of the indicated proteins in MIN6 cell extracts isolated from the time points indicated in d. f qRT-PCR analysis of RNA levels normalized to GAPDH mRNA, for Ins1, Ins2, MafA and Herpud1 mRNAs in the last 2 stress/recovery cycles. n = 3 independent experiments. Error bars represent S.E.M. All comparisons were to sample 1. p-value represents the statistical test by two-tailed paired Student’s t-test. Dots in all plots represent independent experiments. Individual p-values (*) and source data are provided as a Source Data file. g Working hypothesis model of βEAR in T1D pathogenesis.