Nuclear receptor TLX regulates islet beta cell proliferation via E2F6
Nuclear receptor TLX regulates islet beta cell proliferation via E2F6
复制标题
核受体 TLX 通过 E2F6 调节胰岛 β 细胞增殖
DOI：
10.1016/j.bbrc.2019.04.033
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发表时间：
2019-06-04
影响因子：
3.1
通讯作者：
Yang, Yan
中科院分区：
文献类型：
--
作者：
Shi, Xiaoli;Ma, Delin;Yang, Yan
1型和2型糖尿病都与功能性β细胞群的丧失有关，迫切需要恢复β细胞的策略。我们以前报道过核受体TLX的过度表达诱导β细胞增殖，但其潜在的分子机制尚未确定。在这里，我们通过ChIP-Seq在全基因组水平上鉴定了β细胞中TLX的直接靶点。这些目标包括一批众所周知对扩散至关重要的监管机构。在这些ChIP靶标中，E2 F6与细胞周期模块紧密相关，因此，我们进一步分析了E2 F6在β细胞中的表达和功能。我们发现E2 F6被TLX强烈下调，并且其表达抑制β细胞增殖。此外，E2 F6与TLX的共表达部分消除了TLX的增殖作用。这些结果强烈表明TLX通过E2 F6调节β细胞增殖。总之，这项研究的结果揭示了TLX和E2 F6之间的直接相互作用，并提出了扩大功能性β细胞群的新靶点。(C)2019爱思唯尔公司All rights reserved.
Both type 1 and type 2 diabetes are associated with loss of functional beta cell mass, and strategies to restore beta cells are urgently needed. We reported previously that overexpression of the nuclear receptor TLX induces beta cell proliferation, but the underlying molecular mechanism has not been defined. Here, we identified direct targets of TLX in beta cells at the genome-wide level by ChIP-Seq. These targets include a cadre of regulators that are known to be critical for proliferation. Among these ChIP targets, E2F6 was tightly associated with the cell cycle modules, and thus, we further analyzed E2F6 expression and function in beta cells. We showed that E2F6 is strongly downregulated by TLX, and its expression inhibits beta cell proliferation. Moreover, coexpression of E2F6 with TLX partially abrogated the proliferative effects of TLX. These results strongly suggest that TLX acts through E2F6 to regulate beta cell proliferation. Together, the results of this study reveal a direct interaction between TLX and E2F6 and suggest new targets for the expansion of functional beta cell mass. (C) 2019 Elsevier Inc. All rights reserved.