Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks.
Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks.
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DOI：
10.1016/j.cmet.2016.11.016
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发表时间：
2017-02-07
期刊：
影响因子：
29
通讯作者：
Ferrer J
中科院分区：
文献类型：
--
作者：
Akerman I;Tu Z;Beucher A;Rolando DMY;Sauty-Colace C;Benazra M;Nakic N;Yang J;Wang H;Pasquali L;Moran I;Garcia-Hurtado J;Castro N;Gonzalez-Franco R;Stewart AF;Bonner C;Piemonti L;Berney T;Groop L;Kerr-Conte J;Pattou F;Argmann C;Schadt E;Ravassard P;Ferrer J
最近的研究已经在人类胰腺β细胞中发现了数千种长链非编码rna （lncRNAs）。β细胞lncrna通常是细胞类型特异性的，在分化过程中或葡萄糖浓度变化时表现出动态调节。尽管这些特征暗示了lncRNAs在β细胞基因调控和糖尿病中的作用，但β细胞lncRNAs的功能在很大程度上仍然未知。在这项研究中，我们使用转录敲低和共表达网络分析来研究β细胞特异性lncRNAs和转录因子的功能。这揭示了lncRNAs与转录因子协同作用，调节β细胞特异性转录网络。我们进一步证明，lncRNA PLUTO影响局部3D染色质结构和PDX1的转录，编码一个关键的β细胞转录因子，并且PLUTO和PDX1在2型糖尿病或糖耐量受损的供体胰岛中下调。这些结果暗示lncrna参与β细胞特异性转录因子网络的调控。功能缺失筛选揭示功能性β细胞lncRNAs细胞特异性lncRNAs和转录因子调节常见基因网络lncRNA PLUTO影响增强子簇和PDX1之间的相互作用PLUTO和PDX1在2型糖尿病和糖耐量受损中失调Akerman等人通过RNAi、CRISPRi和共表达网络研究了人类β细胞lncRNAs的功能。这揭示了β细胞lncrna和转录因子控制共同的调节网络。其中一个lncRNA PLUTO在2型糖尿病中下调，并控制PDX1，编码一个关键的β细胞转录因子。
Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks. A loss-of-function screen reveals functional β cell lncRNAs Cell-specific lncRNAs and transcription factors regulate common gene networks The lncRNA PLUTO influences interactions between an enhancer cluster and PDX1 PLUTO and PDX1 are deregulated in type 2 diabetes and impaired glucose tolerance Akerman et al. studied the function of human β cell lncRNAs with RNAi, CRISPRi, and co-expression networks. This revealed β cell lncRNAs and transcription factors that control common regulatory networks. One lncRNA, PLUTO, is downregulated in type 2 diabetes and controls PDX1, encoding a key β cell transcription factor.