Epigenetic factors governing SOD2 gene expression

控制 SOD2 基因表达的表观遗传因素

• 批准号: 6804724
• 负责人: FREDERICK E DOMANN
• 金额: $ 26.26万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-06 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804724
• 关键词: CpG islands; DNA methylation; MCF7 cell; acetylation; carcinogenesis; cell differentiation; gene expression; gene induction /repression; genetic transcription; green fluorescent proteins; heterochromatin; histones; immunoprecipitation; neoplasm /cancer genetics; nucleic acid sequence; p53 gene /protein; polymerase chain reaction; regulatory gene; tissue /cell culture; transcription factor; tumor suppressor genes; western blottings

DESCRIPTION (provided by applicant): The long-term objective of this research proposal is to investigate the mechanism(s) by which SOD2 gene expression is altered during differentiation and carcinogenesis with a goal to determine molecular targets for therapeutic intervention that could be used to reactivate this important antioxidant enzyme and tumor suppressor gene. The hypothesis for the proposed research is that SOD2 gene expression is regulated, at least in part, through an epigenetic mechanism involving DNA methylation and/or histone modification of its transcriptional regulatory regions. To test the hypothesis that the human SOD2 gene is regulated by epigenetic events including DNA methylation, histone hypoacetylation, and chromatin accessibility, we propose to pursue the following specific aims: 1) determine whether decreased expression of the SOD2 gene in human cancer cells is causally associated with hypermethylation of the CpG island in the human SOD2 gene; 2) determine whether and to what extent histone modifications including acetylation and/or methylation participate in the transcriptional inhibition of the SOD2 gene in human cancer cells; 3) test the hypothesis that the known regulatory regions of the endogenous SOD2 reside in a closed heterochromatic state in non-expressing human cancer cells; 4) establish the molecular mechanism(s) by which the transcription factor AP-2 leads to the down-regulation of SOD2 expression in human cancer cells; and 5) examine the relationship between p53 and SOD2 expression and to determine the mechanism(s) underlying p53 mediated repression of SOD2 expression. The list of important cancer genes, particularly tumor suppressor genes, whose transcriptional regulation during cancer development is governed at least in part by epigenetic mechanisms including aberrant cytosine methylation, histone hypoacetylation and heterochromatinization makes this an important area of investigation. The proposed studies will not only clarify the specific mechanism(s) by which these epigenetic factors participate in SOD2 regulation, but also provide valuable insight into new avenues for clinical intervention and treatment. As our understanding of epigenetic control of gene expression continues to expand, novel therapeutic approaches targeting this level of gene regulation will undoubtedly emerge. The acknowledged importance of decreased SOD2 expression in cancer makes this a particularly attractive target gene for therapeutic manipulation by pharmacological inhibitors of DNA methyltransferases and histone deacetylases.

描述（由申请人提供）：这项研究建议的长期目标是研究在分化和致癌过程中改变SOD2基因表达的机制，其目标是确定可用于重新激活这种重要的抗氧化剂酶和肿瘤抑制基因的治疗干预的分子靶标。提出的研究的假设是，至少部分通过涉及DNA甲基化和/或组蛋白修饰其转录调节区域的表观遗传机制来调节SOD2基因表达。为了检验人类SOD2基因的假设受到表观遗传事件的调节，包括DNA甲基化，组蛋白低乙酰化和染色质访问性，我们建议追求以下具体目的：1）确定人类癌细胞中SOD2基因表达的降低是否与人类CPG岛人类Sod2 Gene的高甲基化相关性是否与人类甲基化的高度相关。 2）确定包括乙酰化和/或甲基化在内的组蛋白修饰以及在何种程度上参与人类癌细胞中SOD2基因的转录抑制作用； 3）检验以下假设：内源性SOD2的已知调节区域位于非表达人类癌细胞中的封闭异型状态； 4）建立分子机制，通过该机制，转录因子AP-2导致人类癌细胞中SOD2表达的下调； 5）检查p53和SOD2表达之间的关系，并确定p53介导的SOD2表达抑制的机制。重要的癌症基因，尤其是肿瘤抑制基因的清单，其在癌症发育期间的转录调节至少部分受到表观遗传机制的控制，包括异常的胞嘧啶甲基化，组蛋白低乙酰化和异染色性化，使其成为研究的重要领域。拟议的研究不仅将阐明这些表观遗传因素参与SOD2调节的具体机制，而且还为临床干预和治疗的新途径提供了宝贵的见解。随着我们对基因表达的表观遗传控制的理解不断扩展，针对这种基因调节水平的新型治疗方法无疑会出现。癌症中SOD2表达降低的公认的重要性使得这是DNA甲基转移酶和组蛋白脱乙酰基酶的药理抑制剂治疗操作的特别有吸引力的靶基因。