Transcription factor mutationsunderlying birth defects or pediatric cancers

出生缺陷或儿科癌症背后的转录因子突变

• 批准号: 10004146
• 负责人: MARTHA L BULYK
• 金额: $ 17.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004146
• 关键词: Affinity; Binding; Binding Sites; Biochemical; Biological Assay; Biology; Cause of Death; Cell Cycle Regulation; Cells; Child; Childhood; Code; Communities; Congenital Abnormality; DNA; DNA Binding; DNA Damage; Data; Development; Diagnostic; Disease; Funding; Gene Expression; Genetic; Genome; Genomics; Goals; Hospitalization; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Mutation; Pathogenicity; Patients; Pediatric Research; Regulator Genes; Research Personnel; Resources; Specificity; Structural Congenital Anomalies; United States National Institutes of Health; Variant; cost; data resource; genetic variant; insight; large scale data; mutant; phenotypic data; programs; socioeconomics; transcription factor

ABSTRACT The interactions between transcription factor (TFs) and their DNA binding sites are an integral part of the gene regulatory networks within cells. These interactions control critical steps in development and cell cycle control. Mutations in TFs can result in a wide range of structural birth defects or cancers through the dysregulation of gene expression. The Pediatric Data Resource Center established by the Gabriella Miller Kids First (GMKF) Pediatric Research Program (Kids First) provides genome sequence and phenotype data for studies investigating the genetics of childhood cancers or structural birth defects. Analysis of the GMKF data are needed to identify and annotate genetic variants associated with these major pediatric diseases. The goals of this project are: (1) to analyze genome sequence data from patients with structural birth defects made available as part of the Kids First Data Resource to identify genetic variants predicted to damage the ability of TFs to bind their DNA target sequences; and (2) to perform biochemical assays on a prioritized set of the TF coding variants to characterize their putatively damaged DNA binding activities. We anticipate our results will help to identify pathogenic variants contributing to structural birth defects or pediatric cancers, reveal mechanisms by which such variants may dysregulate gene expression leading to these disorders, lead to refined genomic diagnostics, and provide data on the mutant TFs’ altered DNA binding activities as a resource to the community.

抽象的 转录因子 (TF) 与其 DNA 结合位点之间的相互作用是 这些相互作用控制着细胞内基因调控网络的组成部分。 转录因子的发育和细胞周期控制中的关键步骤可能导致广泛的结果。 通过基因失调导致的一系列结构性出生缺陷或癌症 表达。 Gabriella Miller Kids First 建立的儿科数据资源中心 (GMKF) 儿科研究计划（儿童优先）提供基因组序列和 用于研究儿童癌症或结构性癌症遗传学的研究的表型数据 需要对 GMKF 数据进行分析来识别和注释遗传缺陷。 与这些主要儿科疾病相关的变异。 该项目的目标是：（1）分析患有以下疾病的患者的基因组序列数据： 结构性出生缺陷作为“儿童第一”数据资源的一部分提供，以识别 基因变异预计会损害 TF 结合 DNA 靶标的能力 序列；(2) 对一组优先的 TF 编码进行生化分析 变体来表征其假定的受损 DNA 结合活性。 我们预计我们的结果将有助于识别导致 结构性出生缺陷或儿科癌症，揭示了此类变异的机制 可能导致这些疾病的基因表达失调，导致基因组精细化 诊断，并提供突变 TF 的 DNA 结合活性数据作为 向社区提供资源。