H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [RNA-seq]. H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [RNA-seq]

Insufficient insulin release by β-cells is the primary etiology in type 2 diabetes (T2D) and coincides with impaired expression of genes essential to β-cell function, but drivers of gene expression dysregulation are not well resolved. We find that H3K4me3 peak breadth correlates with gene expression dysregulation in T2D. Using an adult β-cell Dpy30-KO mouse model, we show that global reduction of H3K4 methylation causes downregulation of genes also downregulated in T2D. Reduction of H3K4 methylation increases transcriptional entropy and reduces insulin production and glucose-responsiveness. Depletion of H3K4 methylation causes global dilution of epigenetic complexity but does not generally reduce gene expression – instead, genes related to β-cell function and/or in particular chromatin environments are specifically affected. Our data further suggests that promoter-associated H3K4me1 is sufficient to maintain expression in the absence of H3K4me3. These data implicate dysregulation of H3K4 methylation in destabilizing gene expression and contributing to β-cell dysfunction in T2D. Overall design: RNA-seq of 3 replicates at 2 time points, scRNA-seq of 1 replicate at 1 time point, from Dpy30-KO or CTRL mouse beta cells Please note that the "scRNAseq_commands.txt" contains the processing pipeline details to regenerate the processed data from raw data for scRNA-seq. The file "mtmg_long.fa" containing egfp and tdtomato sequences is necessary to regenerate the processed data.

β细胞胰岛素分泌不足是2型糖尿病（T2D）的核心病因，同时伴随β细胞功能必需基因的表达受损，但基因表达失调的驱动机制尚未完全明晰。我们发现，H3K4me3峰宽度与2型糖尿病中的基因表达失调显著相关。本研究利用成年β细胞Dpy30敲除（Dpy30-KO）小鼠模型，证实全基因组H3K4甲基化水平降低会诱导在2型糖尿病中同样出现下调的基因发生表达下调。H3K4甲基化水平降低会增加转录熵，同时降低胰岛素产生能力与葡萄糖应答性。H3K4甲基化缺失会导致表观遗传复杂性的全基因组稀释，但并未普遍降低基因表达；相反，与β细胞功能相关的基因以及处于特定染色质环境的基因会受到特异性影响。我们的数据进一步表明，在缺乏H3K4me3的情况下，启动子结合的H3K4me1足以维持基因表达。上述数据表明，H3K4甲基化失调会破坏基因表达稳定性，并参与2型糖尿病中β细胞功能障碍的发生。实验整体设计：对Dpy30敲除（Dpy30-KO）或对照（CTRL）小鼠β细胞，在2个时间点各设置3次生物学重复进行RNA测序（RNA-seq），并在1个时间点开展1次生物学重复的单细胞RNA测序（scRNA-seq）。请注意，"scRNAseq_commands.txt"文件包含了从原始数据重新生成scRNA-seq处理后数据的分析流程细节；包含egfp与tdtomato序列的"mtmg_long.fa"文件，是重新生成处理后数据的必需文件。