Epigenetic Regulation of Mitochondiral Complex II

描述（由申请人提供）：编码线粒体复合体II的四个亚基中的三个的基因遗传突变导致遗传性副神经节瘤（PGL）的家族性易感性。PGL的特点是发生在头颈部和腹部的血管化肿瘤，起源于氧感应细胞。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。由名为sddd的基因编码的复合体II最小亚基突变是头颈部副神经节瘤的主要原因。当基因突变从父亲遗传给孩子时，会导致肿瘤，但如果基因突变从母亲遗传，则不会导致肿瘤的发生。这种现象被称为基因组印记。基因组印记导致基因的功能差异取决于其亲本来源。PGL的印迹机制尚不清楚。了解基因组印记在PGL中的作用机制是很重要的，因为基因组印记决定了突变携带者是否会患多种肿瘤或终生保持完全无肿瘤。虽然还有其他疾病受基因组印记的影响，但PGL是独特的，因为基因组印记对单个突变基因的影响导致疾病或完全正常。本应用主要旨在研究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，这些通常在其他印迹基因周围观察到。这些分子标记经常区分一个印迹基因的母系和父系拷贝。我们还将研究另一种基因控制机制，称为转录编辑，作为控制细胞中线粒体复合体II数量的另一种手段。了解PGL中印迹的分子基础可以为单个缺陷基因的差异表达如何导致疾病或正常提供一般见解。

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.