Genes associated with endocrine tumorigenesis

由MEN1基因编码的脑膜素功能失活会导致遗传性多发性内分泌瘤1型(MEN1)综合征和一些但不是所有散发性胰腺内分泌肿瘤。因此，解开薄荷素上游或下游的分子事件可能指向导致这种肿瘤类型的其他致病基因和/或调控事件。Menin存在于组蛋白甲基化蛋白复合体中，它使组蛋白H3在赖氨酸-4(H3K4me3)上三甲基化，赖氨酸-4(H3K4me3)是活跃基因表达的表观遗传标记。因此，我们通过体外分化，在野生型和脑膜素缺失的小鼠胚胎干细胞(WT)和胰岛样内分泌细胞(PILECs)中确定了依赖脑膜素的H3K4me3的全基因组图谱(使用CHIP-Seq)和脑膜素依赖的基因表达程序。我们在小鼠ESCs中发现了针对Meg3基因的依赖于menin的H3K4me3，在分化的PILECs中发现了所有四个Hox基因座。在脑膜素缺失的细胞中，来自Meg3基因座和所有四个HOX基因座的基因表达被取消。MEN1样散发性肿瘤与Meg3和Hox基因座均有关联：MEG3基因与垂体肿瘤相关，而Hox基因与甲状旁腺肿瘤相关。我们的数据表明，这些依赖于脑膜素的H3K4me3基因可能在与MEN1相关的内分泌细胞类型的肿瘤发生中发挥相关作用。此外，我们的工作表明，脑膜素缺失的小鼠胚胎干细胞也可以在体外分化为胰岛样内分泌细胞，这突显了脑膜素缺失的胚胎干细胞来源的专门细胞类型在全基因组分析研究中的作用。我们目前的努力是为了了解MEG3和HOX基因座的基因调控和活性。 我们已经证明，负调控细胞周期进程和细胞增殖的INK4家族(4个基因)和Cip/Kip家族(3个基因)的细胞周期蛋白依赖性激酶抑制物(CDKI)在与MEN1相关的内分泌肿瘤状态中具有罕见的种系或体细胞突变。此外，小鼠模型在CDK4-R24C突变纯合子或两个不同CDKI p18和p27联合缺失的“敲入”小鼠中显示出内分泌肿瘤表型。因此，了解CDK和CDKI调控的分子基础可以深入了解它们在内分泌肿瘤发生中的作用。我们研究了细胞周期调节因子在内分泌肿瘤发生中的作用，特别是CDKI基因的突变。我们感兴趣的是研究内分泌细胞细胞周期调控的分子基础。

Functional inactivation of menin, encoded by the MEN1 gene, causes the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome and some but not all sporadic pancreatic endocrine tumors. Therefore, unraveling molecular events upstream or downstream of menin could point to other causative genes and/or regulatory events responsible for such tumor types. Menin resides in a histone methylating protein complex that trimethylates histone H3 at lysine-4 (H3K4me3), an epigenetic mark for active gene expression. Therefore, we have determined a genome-wide map of menin-dependent H3K4me3 (using ChIP-Seq) and menin-dependent gene-expression program in wild-type (WT) and menin-null mouse embryonic stem cells (ESCs) and in pancreatic islet-like endocrine cells (PILECs), which we derived from WT and menin-null mouse ESCs through in vitro differentiation. We found menin-dependent H3K4me3 specifically targeting the Meg3 gene in mouse ESCs, and all four Hox loci in differentiated PILECs. Gene expression from the Meg3 locus and from all of the four Hox loci was abolished in menin-null cells. Both Meg3 and Hox loci have been implicated in MEN1-like sporadic tumors: MEG3 in pituitary tumors, and HOX in parathyroid tumors. Our data suggest that these genes with menin-dependent H3K4me3 could be relevant players in the tumorigenesis of endocrine cell types associated with MEN1. Furthermore, our work shows that menin-null mouse ESCs could also be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null ESC-derived specialized cell types for genome-wide analyses studies. Our current efforts are directed towards understanding the regulation and activity of genes at the MEG3 and HOX loci. We have shown that cyclin-dependent kinase inhibitors (CDKIs) of the INK4 family (4 genes) and the Cip/Kip family (3 genes) that negatively regulate cell cycle progression and cell proliferation have rare germline or somatic mutations in endocrine tumor states related to MEN1. Also, mouse models show an endocrine neoplasia phenotype in 'knock-in' mice homozygous for the CDK4-R24C mutation, or by the combined loss of two different CDKIs, p18 and p27. Therefore, understanding the molecular basis of CDK and CDKI regulation could provide insights into their contribution to endocrine tumorigenesis. We have investigated the contribution of cell cycle regulators in endocrine tumorigenesis, particularly mutations in CDKI genes. We are interested in investigating the molecular basis of cell cycle regulation in endocrine cells.