Chromatin reorganization drives expression of functional maturation genes in senescent pancreatic beta cells (Series2 - chromatin sccessibility, ATAC-seq). Chromatin reorganization drives expression of functional maturation genes in senescent pancreatic beta cells (Series2 - chromatin sccessibility, ATAC-seq)

Using a unique model of cultured human beta cell senescence we show that chromatin reorganization leads to activation of enhancers regulating functional maturation genes, concomitantly with acquisition of glucose-stimulated insulin secretion capacity. Interferon-response genes are elevated in senescent beta cells, but cytokine-encoding senescence-associated secretory phenotype (SASP) genes are not. Human beta cell senescence thus involves chromatin-driven upregulation of a functional maturation program and of interferon-stimulated genes, changes that could increase both insulin secretion and immune reactivity. Overall design: Chromatin accessibility profiles of non-senescent and senescent state of human pancreatic beta-like cells in culture.

本研究利用一种独特的体外培养人β细胞衰老模型，证实染色质重塑可激活调控功能成熟相关基因的增强子，同时伴随葡萄糖刺激胰岛素分泌能力的获得。研究发现，衰老β细胞中干扰素应答基因表达上调，但编码细胞因子的衰老相关分泌表型（senescence-associated secretory phenotype, SASP）基因则未出现此类变化。由此可见，人β细胞衰老过程涉及染色质介导的功能成熟程序与干扰素刺激基因的上调，这类变化可同时增强胰岛素分泌与免疫反应性。实验整体设计：获取体外培养的人胰腺β样细胞在非衰老与衰老状态下的染色质可及性谱。