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. 2023 Mar 13;66(6):1097–1115. doi: 10.1007/s00125-023-05896-6

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — H3K4me3 peak breadth encodes gene expression changes in a mouse model of type 2 diabetes. (a) H3K4me3 peaks in Dpy30-WT beta cells ranked from narrow to broad. Peaks associated with beta cell transcription factor genes are labelled. (b) Genome browser views showing H3K4me3 at a housekeeping gene (Rplp0) and an expression-matched beta cell transcription factor gene (Nkx6-1). (c) Enrichment p values of genes down- or upregulated in islets from Lepr^db/db mice, with genes ranked by H3K4me3 peak breadth (as in [a]) and grouped into 20 quantiles. P values were calculated using one-sided Fisher’s exact tests. (d, e) The same data as in (a, b) for human beta cells. (f) Enrichment p values of genes down- or upregulated in islets from donors with type 2 diabetes, with genes ranked by H3K4me3 peak breadth (as in [d]) and grouped into 20 quantiles. P values were calculated using one-sided Fisher’s exact tests. (g) Immunoblots of H3K4me3 and H3 in islet lysates from Lepr^+/+ and Lepr^db/db mice. H3-normalised H3K4me3 band densities are listed. (h) Average enrichment profiles of H3K4me3 at the TSS of all expressed genes in Lepr^+/+ and Lepr^db/db islets. (i) Genome browser views of H3K4me3 in Lepr^+/+ and Lepr^db/db islets at notable genes that are downregulated (Pdx1, Slc30a8) or induced (Aldh1a3, Ldha) in Lepr^db/db islets. (j) Enrichment p values of H3K4me3 peaks showing significant change in peak breadth in Lepr^db/db vs Lepr^+/+ islets (y axis) in the different gene groups ranked from narrow to broad (x axis). Enrichment p values were calculated using one-sided Fisher’s exact tests. (k) Box and whisker plot showing the log₂(fold change) in H3K4me3 peak breadth for genes that are downregulated, stably expressed and upregulated in Lepr^db/db islets. P values were calculated using Wilcoxon rank-sum tests with Benjamini–Hochberg correction. ***p<0.001. (l) Stratified rank/rank hypergeometric overlap plot comparing gene expression changes caused by Dpy30-KO (x axis) and by Lepr^db/db (y axis) mutations. Colourscale shows the hypergeometric enrichment p value. (m) Same as (c) for genes down- or upregulated in Dpy30-KO cells