Epigenetic Regulation of Mitochondiral Complex II

线粒体复合物 II 的表观遗传调控

• 批准号: 7548624
• 负责人: GERALD SHADEL
• 金额: $ 20.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7548624
• 关键词: Abdomen; Adrenal Medulla; Alleles; Altitude; Carotid Body; Cells; Child; Complex; Constitutional; Corpora paraaortica; DNA; DNA Methylation; Data; Defect; Development; Disease; Epigenetic Process; Etiology; Fathers; Gene Expression; Gene Expression Regulation; Genes; Genomic Imprinting; Germ Lines; Head and Neck Paraganglioma; Head and neck structure; Health; Hereditary Paraganglioma; Hypoxia Inducible Factor; Impairment; Inherited; Lead; Methylation; Mitochondria; Molecular; Mothers; Mutate; Mutation; Names; Normal tissue morphology; Normalcy; Operative Surgical Procedures; Oxygen; Paraganglioma; Parents; Penetrance; Play; Population Genetics; Predisposition; Production; RNA Editing; Regulation; Role; Succinate Dehydrogenase; System; Testing; Tissues; Transcript; base; disease transmission; gene function; imprint; insight; mutation carrier; novel; overexpression; transmission process; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Inherited mutations in genes encoding three of the four subunits of mitochondrial complex II cause familial predisposition to hereditary paraganglioma (PGL). PGL is characterized by the development of vascularized tumors, in the head and neck and abdomen, and derive from oxygen sensing cells. How mitochondrial defects could lead to tumor formation is a mystery, because mitochondria are primarily involved in energy production. Mutations in the smallest subunit of complex II, encoded by a gene named SDHD, are the primary cause of head and neck paragangliomas. Mutations in SDHD cause tumors when they are transmitted from a father to his children, but no tumor development is seen if the mutations are transmitted from a mother. This phenomenon is known as genomic imprinting. Genomic imprinting causes differences in the function of genes depending on its parental origin. The mechanism of imprinting in PGL is unknown. Understanding the mechanism of genomic imprinting in PGL is important because genomic imprinting determines whether a mutation carrier will suffer from multiple tumors or remain entirely tumor-free lifelong. Although there are other disorders that are influenced by genomic imprinting, PGL is unique because impact of genomic imprinting on a single mutated gene leads to either disease or to complete normalcy. This application primarily proposes to study molecular basis of genomic imprinting in PGL. The specific aims include determination of molecular signs of genomic imprinting such as gene expression and DNA methylation differences, which are commonly observed around other imprinted genes. These molecular signs often distinguish the maternal and paternal copies of an imprinted gene. We will also study another mechanism of gene control, called transcript editing, as another means of controlling the amount of mitochondrial complex II in the cell. Understanding the molecular basis of imprinting in PGL may provide general insights on how differential expression of a single defective gene can lead to disease or normalcy.

描述（申请人提供）：编码线粒体复合体II四个亚基中三个亚基的基因的遗传突变导致遗传性副神经节瘤（PGL）的家族易感性。PGL的特征在于在头部、颈部和腹部发展血管化肿瘤，并且源自氧敏感细胞。线粒体缺陷如何导致肿瘤形成是一个谜，因为线粒体主要参与能量产生。由一个名为SDHD的基因编码的复合体II的最小亚基的突变是头颈部副神经节瘤的主要原因。当SDHD突变从父亲传给孩子时会导致肿瘤，但如果突变从母亲传给孩子，则不会发生肿瘤。这种现象被称为基因组印记。基因组印记导致基因功能的差异取决于其亲本来源。PGL中的印迹机制尚不清楚。了解PGL中基因组印记的机制很重要，因为基因组印记决定了突变携带者是否会患有多种肿瘤或终身保持完全无肿瘤。虽然有其他疾病的影响，基因组印记，PGL是独特的，因为基因组印记的影响，对一个单一的突变基因导致疾病或完全正常。本申请主要研究PGL基因组印迹的分子基础。具体目标包括确定基因组印迹的分子标志，如基因表达和DNA甲基化差异，这通常在其他印迹基因周围观察到。这些分子标志通常区分一个印记基因的母本和父本拷贝。我们还将研究另一种基因控制机制，称为转录本编辑，作为控制细胞中线粒体复合物II数量的另一种手段。了解PGL中印迹的分子基础可能会提供关于单个缺陷基因的差异表达如何导致疾病或正常的一般见解。