Genes associated with endocrine tumorigenesis

MEN1基因编码的menin功能失活可导致遗传性多发性内分泌肿瘤1型（MEN1）综合征和部分散发性胰腺内分泌肿瘤。因此，解开menin上游或下游的分子事件可以指向其他致病基因和/或负责此类肿瘤类型的调节事件。Menin存在于一个组蛋白甲基化蛋白复合体中，该复合体在赖氨酸-4 （H3K4me3）上三甲基化组蛋白H3，赖氨酸-4是活跃基因表达的表观遗传标记。因此，我们已经确定了menin依赖性H3K4me3的全基因组图谱（使用ChIP-Seq）和menin依赖性基因表达程序在野生型（WT）和menin-null小鼠胚胎干细胞（ESCs）和胰岛样内分泌细胞（PILECs）中，我们通过体外分化从WT和menin-null小鼠ESCs中获得。我们发现menin依赖性H3K4me3特异性靶向小鼠ESCs中的Meg3基因，以及分化的pilec中的所有四个Hox位点。在menin-null细胞中，Meg3位点和所有四个Hox位点的基因表达均被消除。Meg3和Hox基因座都与men1样散发性肿瘤有关：Meg3在垂体肿瘤中，Hox在甲状旁腺肿瘤中。我们的数据表明，这些具有menin依赖性H3K4me3的基因可能与MEN1相关的内分泌细胞类型的肿瘤发生有关。此外，我们的工作表明，menin-null小鼠ESCs也可以在体外分化为胰岛样内分泌细胞，这强调了menin-null ESCs衍生的特化细胞类型在全基因组分析研究中的实用性。我们目前的工作方向是了解MEG3和HOX位点基因的调控和活性。

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.