menin促进肝癌恶性表型的组蛋白甲基化机制研究

Menin, encoded by Men1 gene, plays a vital role in cell phenotype regulation, such as proliferation and differentiation. Mutations or activation of Men1 gene result in endocrine tumor or human acute leukemias with very poor prognosis. It is based on transcriptional control and chromatin histone modification at target gene promoter locus by menin. Our previous results suggest that menin regulates Histone 3 lysine 4 (H3K4) methylation and target gene transcription in hepatocellular carcinoma (HCC), and contributes to promotting HCC development and malignant phenotype, acts as a pro-oncogene function. In the present study, we focus on uncover a vital oncogenic role and epigenetic mechanisms of menin in HCC system. Firstly, we use Men1 gene knockout mice to establish primary HCC disease model, to further invastigates the oncogenic function of menin in controlling the malignant phenotype at HCC development progress, and systematic observe the pathological characteristics. Secondly, we based on data integration analysis of previous obtained microarray and ChIP-on-ChIP results, to screen and identify the menin regulated essential target gene and pathway network, and verify the vital role in controlling HCC phenotype. Thirdly, we using ChIP and other key approach to in-depth discuss how menin regulates target gene transcription. We will clarify Histone 3 lysine 4 methylation mechanism of target gene transcriptional regulation by menin/MLL Histone Methyltransferase complex, exactly identify histone Methyltransferase complex component, and further confirm the key role that menin mediated histone modification enzyme system in the process of developing HCC. Above results will help to reveal a novel epigenetic mechanism for the menin promoting HCC devolopment and melignant phenotype.

Men1基因的编码蛋白menin通过组蛋白甲基化等表观遗传学机制调控靶基因转录，广泛参与细胞增殖、分化等关键细胞表型调控，是白血病、内分泌肿瘤等疾病的关键致病基因。最近我们发现，menin调控的组蛋白甲基化修饰、靶基因转录与肝癌发病有关，可能是肝癌重要的促癌基因之一。本研究拟从已获得的基因表达谱和组蛋白甲基化组学数据的整合性分析入手，利用Men1基因敲除小鼠建立的原发性肝癌等疾病模型，采用ChIP等关键技术，系统探讨menin调控肝癌恶性表型、促进原发性肝癌发生发展的时程规律和病理学特点；筛选和鉴定肝癌中menin调控的关键靶基因及其信号网络，探讨其生物学意义；阐明menin调控靶基因转录的H3K4等组蛋白甲基化机制，鉴定肝癌系统中menin/MLL组蛋白甲基化酶复合物组成；证实menin介导的组蛋白甲基化在肝癌发病过程中的关键促进作用,将有助于揭示肝癌发生的崭新表观遗传学机制。

Men1基因的编码蛋白menin通过组蛋白甲基化等表观遗传学机制调控靶基因转录，广泛参与细胞增殖、分化等关键细胞表型调控，是白血病、内分泌肿瘤等疾病的关键致病基因。最近我们发现，menin调控的组蛋白甲基化修饰与靶基因转录调控参与肝癌发病，可能是肝癌重要的促癌基因之一。本研究从已获得的基因表达谱和组蛋白甲基化组学数据的整合性分析入手，通过建立Men1基因敲除小鼠原发性肝癌等疾病模型，系统探讨了menin/MLL组蛋白甲基化酶调控肝癌恶性表型的规律和特点；筛选和鉴定了menin调控的关键靶基因及其信号网络；阐明肝脏系统中menin调控靶基因转录的规律、组蛋白修饰特点及组蛋白甲基化酶复合物组成；证实menin介导的组蛋白修饰酶系统在肝癌发病过程中的关键促癌作用。这将有助于阐明有关肝癌发生的崭新的表观遗传学机制及其信号通路，扩展对menin介导的组蛋白修饰特点、规律等领域的认识，对menin通路为靶点的肝癌早期诊断和治疗具有积极的指导意义。