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Specific Silencing of the REST Target Genes in Insulin-Secreting Cells Uncovers Their Participation in Beta Cell Survival

机译：在胰岛素分泌细胞的REsT靶基因的特异性沉默揭阳及其在β细胞存活参与

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The absence of the transcriptional repressor RE-1 Silencing Transcription Factor (REST) in insulin-secreting beta cells is a major cue for the specific expression of a large number of genes. These REST target genes were largely ascribed to a function of neurotransmission in a neuronal context, whereas their role in pancreatic beta cells has been poorly explored. To identify their functional significance, we have generated transgenic mice expressing REST in beta cells (RIP-REST mice), and previously discovered that REST target genes are essential to insulin exocytosis. Herein we characterized a novel line of RIP-REST mice featuring diabetes. In diabetic RIP-REST mice, high levels of REST were associated with postnatal beta cell apoptosis, which resulted in gradual beta cell loss and sustained hyperglycemia in adults. Moreover, adenoviral REST transduction in INS-1E cells led to increased cell death under control conditions, and sensitized cells to death induced by cytokines. Screening for REST target genes identified several anti-apoptotic genes bearing the binding motif RE-1 that were downregulated upon REST expression in INS-1E cells, including Gjd2, Mapk8ip1, Irs2, Ptprn, and Cdk5r2. Decreased levels of Cdk5r2 in beta cells of RIP-REST mice further confirmed that it is controlled by REST, in vivo. Using siRNA-mediated knock-down in INS-1E cells, we showed that Cdk5r2 protects beta cells against cytokines and palmitate-induced apoptosis. Together, these data document that a set of REST target genes, including Cdk5r2, is important for beta cell survival.
机译：分泌胰岛素的β细胞中不存在转录抑制因子RE-1沉默转录因子（REST）是大量基因特异性表达的主要提示。这些REST靶基因很大程度上归因于神经元环境中的神经传递功能，而对它们在胰腺β细胞中的作用却很少进行研究。为了确定它们的功能重要性，我们已经生成了在β细胞中表达REST的转基因小鼠（RIP-REST小鼠），并且先前发现REST靶基因对于胰岛素的胞吐作用至关重要。在这里，我们表征了以糖尿病为特征的新型RIP-REST小鼠。在糖尿病性RIP-REST小鼠中，高水平的REST与出生后的β细胞凋亡相关，从而导致成年人的β细胞逐渐丢失和持续的高血糖症。此外，INS-1E细胞中腺病毒REST转导导致对照条件下细胞死亡增加，并使细胞对由细胞因子诱导的死亡敏感。筛选REST靶基因可鉴定出几种带有结合基序RE-1的抗凋亡基因，这些基因在REST-1在INS-1E细胞中表达后被下调，包括Gjd2，Mapk8ip1，Irs2，Ptprn和Cdk5r2。 RIP-REST小鼠的β细胞中Cdk5r2的水平降低进一步证实了它在体内受REST控制。在INS-1E细胞中使用siRNA介导的敲低，我们显示Cdk5r2保护β细胞免受细胞因子和棕榈酸酯诱导的细胞凋亡。这些数据在一起证明，一组REST目标基因（包括Cdk5r2）对于β细胞存活很重要。

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