Analysis of Novel Histone Methylase MLL Function for Glucose Metabolism in Mouse Pancreas
Analysis of Novel Histone Methylase MLL Function for Glucose Metabolism in Mouse Pancreas
复制标题
新型组蛋白甲基化酶 MLL 对小鼠胰腺葡萄糖代谢的功能分析
DOI：
10.1210/jendso/bvab048.646
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发表时间：
2021-05-03
影响因子：
4.1
通讯作者：
Yamada M
中科院分区：
文献类型：
--
作者：
Yoshino S;Ishida E;Horiguchi K;Matsumoto S;Nakajima Y;Yamada E;Okada S;Yamada M
背景）髓系/髓系或混合系白血病基因（MLL）位于11号染色体长臂q23区（11 q23），易位重建后表达的MLL融合基因在MLL相关白血病的发生发展中起重要作用。MLL和MLL蛋白在多发性内分泌瘤I型（MEN 1）中作为Menin结合蛋白在肿瘤发展中起重要作用。最近，正常MLL蛋白已被证明具有组蛋白H3赖氨酸4-甲基化（H3 K4-HMT）活性，并且是表观遗传转录调节因子。此外，MLL蛋白作为组蛋白甲基化酶的功能已被报道在参与代谢区域的基因区域中。在这里，我们分析了参与MLL的葡萄糖代谢在胰腺中使用MLL基因敲除小鼠。方法：）分析MLL基因敲除小鼠的糖代谢及培养细胞中MLL的功能。结果）由于MLL基因敲除小鼠的纯合子是胚胎致死的，我们用杂合子小鼠对它们进行了分析。与野生型小鼠相比，MLL杂合小鼠显示出显著的体重减轻。与野生型小鼠相比，MLL杂合小鼠的摄食量没有差异。IPGTT显示MLL杂合子小鼠的糖耐量受损。然而，ITT在葡萄糖负荷期间未显示胰岛素抵抗和胰岛素分泌减少。在GSIS测试中，已经观察到从杂合小鼠胰腺分离的胰岛响应于葡萄糖刺激而减少胰岛素分泌。利用基因芯片技术对小鼠胰岛mRNA进行综合基因分析，揭示了MLL杂合子小鼠胰岛素分泌和细胞凋亡相关基因表达的变化。组织学检索显示β细胞数量未减少，免疫组织学检索显示杂合子和野生型小鼠之间的胰岛素、胰高血糖素和TUNEL染色无差异。此外，在培养的细胞系中进行MLL敲低。胰岛素分泌减少葡萄糖刺激MLL敲除细胞系在MLL敲除小鼠相同。此外，对这些细胞系进行了RNA微阵列分析，在MLL敲除细胞中观察到了几个与MLL小鼠胰岛中已证实的基因相同的基因。总之，MLL敲除小鼠显示胰岛素分泌减少。提示MLL可能参与胰岛的胰岛素分泌。
Background) Myeloid / Lymphoid or Mixed-lineage leukemia gene (MLL) is translocated to chromosome 11 long arm q23 region (11q23) and the MLL fusion gene expressed as a result of translocation reconstruction plays an important role in MLL-related leukemia development. It has also been reported that MLL and MLL protein play an important role in tumor development as a Menin-binding protein in Multiple Endocrine Neoplasia Type I (MEN1). More recently, normal MLL protein has been shown to have histone H3 lysine 4-methylation (H3K4-HMT) activity and to be an epigenetic transcriptional regulator. In addition, the function of MLL protein as a histone methylase has been reported in the gene region involved in metabolism regions. Here, we analyzed the involvement of MLL in glucose metabolism in the pancreas using MLL knockout mice. Methods:) Glucose metabolism in MLL knockout mice and the function of MLL in cultured cells were analyzed. Result) Since the homozygotes of MLL knockout mice are embryonic lethal, we analyzed them using Heterozygous mice. MLL heterozygous mice showed significantly weight loss compared to the wild type mice. MLL heterozygous mice showed no difference in food intake compared to wild type mice. IPGTT showed impaired glucose tolerance in MLL heterozygous mice. However, ITT showed no insulin resistance and decreased insulin secretion during glucose loading. In GSIS tests, Islets isolated from heterozygous mice pancreas have been observed to decrease insulin secretion in the response to glucose stimulation. In comprehensive gene analysis using Microarray analysis of mRNA extracted from mice islet, the gene expression changes related insulin secretion and apoptosis have been revealed in MLL heterozygous mice. Histological search showed no decrease in β-cell number, and immunohistological search showed no difference in insulin, glucagon, and TUNEL staining between heterozygous and wild type mice. And also, MLL knockdown was performed in a cultured cell line. Insulin secretion was decreased to glucose stimulation in MLL knockdown cell line same as in MLL knockout mice. In addition, RNA microarrays were performed to these cell lines, several same genes that have confirmed in MLL mouse islets were observed in MLL knockdown cell. In conclusion, MLL knockout mice showed decreased insulin secretion. It was suggested that MLL may be involved in insulin secretion in islets.