The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes.
The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes.
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DOI：
10.1016/j.cmet.2018.04.013
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发表时间：
2018-06-05
期刊：
影响因子：
29
通讯作者：
Pospisilik JA
中科院分区：
文献类型：
--
作者：
Lu TT;Heyne S;Dror E;Casas E;Leonhardt L;Boenke T;Yang CH;Sagar;Arrigoni L;Dalgaard K;Teperino R;Enders L;Selvaraj M;Ruf M;Raja SJ;Xie H;Boenisch U;Orkin SH;Lynn FC;Hoffman BG;Grün D;Vavouri T;Lempradl AM;Pospisilik JA
迄今为止，在很大程度上仍然不清楚染色质机制在多大程度上有助于复杂疾病的易感性和进展。在这里，我们结合联合收割机深表观基因组作图与单细胞转录组学来挖掘2型糖尿病中染色质失调的证据。我们发现了两个跟踪小鼠和人类β细胞功能障碍的染色质状态特征：二价Polycomb沉默结构域的异位激活和表观基因组独特的谱系定义基因的表达丧失。小鼠中β细胞特异性Polycomb（Eed/PRC 2）功能丧失触发糖尿病模拟转录特征和高度渗透性、高血糖非依赖性去分化，表明PRC 2失调促成疾病。这项工作为探索β细胞转录调控提供了新的资源，并将PRC 2鉴定为长期维持β细胞身份所必需的。重要的是，数据表明糖尿病中β细胞身份丧失的两次打击（染色质和高血糖症）模型。T2 D中β细胞的深度表观基因组作图和单细胞转录组学人类和小鼠糖尿病模拟PRC 2功能丧失Eed/PRC 2保障终末分化β细胞中的转录完整性Eed/PRC 2敏感的去分化是可靶向的Lu et al.提供了小鼠和人类2型糖尿病中染色质失调的证据。小鼠胰腺中Polycomb沉默的丧失触发β细胞和糖尿病的高血糖非依赖性去分化，表明糖尿病中β细胞身份丧失的两次打击（染色质和高血糖）模型。
To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track β cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. β cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring β cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of β cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes. Deep epigenome mapping and single-cell transcriptomics of β cells in T2D Human and mouse diabetes mimic PRC2 loss of function Eed/PRC2 safeguards transcription integrity in terminally differentiated β cells Eed/PRC2-sensitive dedifferentiation is pharmacologically targetable Lu et al. provide evidence of chromatin dysregulation in type 2 diabetes in mice and humans. Loss of Polycomb silencing in mouse pancreas triggers hyperglycemia-independent dedifferentiation of β cells and diabetes, suggesting a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes.
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