Global Identification of Disease-Associated Genes in Fragile X Cells
Abstract
The proposed research project addresses the Fiscal Year 2014 Peer Reviewed Medical Research Program Topic Area, Fragile X syndrome (FXS). FXS is responsible for the most common form of hereditary mental retardation in the world. Previous studies have established that in most cases FXS is caused by the absence of a protein named FMRP. It is generally believed that FMRP functions in regulating protein production of specific gene targets in the cytoplasm. However, we know that FMRP shuttles between the nucleus and the cytoplasm. To this date, the potential functions of FMRP in the nucleus have not been well examined. We had made a chance discovery that fragile X cells lacking FMRP show high level of chromosome breaks specifically at DNA sequences that are prone to form hybrid molecules of DNA and RNA during gene transcription. This finding led us to propose that FMRP binds to its substrates directly on the chromatin (in the nucleus) and ensures that during their transcription the DNA templates do not form stable DNA:RNA hybrids. The hybrid molecules are impediments to the DNA replication machinery and upon their collision chromosomes are more prone to break, ultimately affecting gene expression and/or protein production of genes near the chromosome breaks. We propose to directly test this hypothesis by querying the genome for FMRP binding sites. These experiments will allow us to identify those specific gene substrates of FMRP, particularly those expressed in the brain, that are implicated in FXS progression. Moreover, we use an innovative tool to directly map chromosome breaks on a genome-wide scale. These proposed experiments will yield a novel list of FXS-associated genes and provide a foundation for future research examining the mechanisms of FXS pathology.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510204
Entities
People
- Wenyi Feng
Organizations
- State University of New York Upstate Medical University
- United States Army