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.

Public Health Relevance

Structural birth defects and pediatric cancers are leading causes of death and hospitalization of children in the U.S. and have significant socioeconomic costs. We will analyze genome sequence data from patients with structural birth defects or pediatric cancers made available as part of the Kids First Data Resource in order to identify genetic variants that are predicted to damage the ability of transcription factors to bind their DNA target sequences in the genome. We will perform biochemical assays on a prioritized set of such variants to characterize their putatively damaged DNA binding activities.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD099358-02
Application #
10004146
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Coulombe, James N
Project Start
2019-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115