https://ror.org/00r9w3j27 Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Life Sci Alliance. 2024 Jun 14;7(8). doi: 10.26508/lsa.202302099. Print 2024 Aug.
A lack of social relationships is increasingly recognized as a type 2 diabetes (T2D) risk. To investigate the underlying mechanism, we used male KK mice, an inbred strain with spontaneous diabetes. Given the association between living alone and T2D risk in humans, we divided the non-diabetic mice into singly housed (KK-SH) and group-housed control mice. Around the onset of diabetes in KK-SH mice, we compared H3K27ac ChIP-Seq with RNA-Seq using pancreatic islets derived from each experimental group, revealing a positive correlation between single-housing-induced changes in H3K27ac and gene expression levels. In particular, single-housing-induced H3K27ac decreases revealed a significant association with islet cell functions and GWAS loci for T2D and related diseases, with significant enrichment of binding motifs for transcription factors representative of human diabetes. Although these H3K27ac regions were preferentially localized to a polymorphic genomic background, SNVs and indels did not cause sequence disruption of enriched transcription factor motifs in most of these elements. These results suggest alternative roles of genetic variants in environment-dependent epigenomic changes and provide insights into the complex mode of disease inheritance.
社交关系缺乏日益被认为是 2 型糖尿病（T2D）的一个风险因素。为了探究其潜在机制，我们使用了雄性 KK 小鼠，这是一种具有自发性糖尿病的近交系。鉴于独居与人类 T2D 风险之间的关联，我们将非糖尿病小鼠分为独居饲养（KK-SH）和群居对照小鼠。在 KK-SH 小鼠糖尿病发病前，我们使用来自每个实验组的胰岛进行了 H3K27ac ChIP-Seq 与 RNA-Seq 的比较，揭示了 H3K27ac 诱导的单一饲养变化与基因表达水平之间的正相关。特别是，与胰岛细胞功能和 T2D 及相关疾病的 GWAS 位点显著相关的 H3K27ac 诱导的单一饲养减少，具有人类糖尿病代表性转录因子结合基序的显著富集。尽管这些 H3K27ac 区域优先定位于多态性基因组背景，但在大多数这些元件中，SNVs 和 indels 并未导致富集转录因子基序的序列破坏。这些结果表明遗传变异在环境依赖的表观遗传变化中的替代作用，并为疾病遗传的复杂模式提供了见解。
