Interchromosomal Associations that Alter Nf1 Gene Expression can Modify Clinical Manifestations of Neurofibromatosis 1
Abstract
We have described a new form of epistasis in which direct, long range, physical interactions between genes, or gene-gene interactions mediated by specialized DNA binding proteins such as CTCF, lead to modification of phenotypic read-out. Using the associated chromatin trap (ACT) and chromosome conformation capture (3C) assays which are designed to assess physical propinquity, we investigated long range interactions of the human NF1 gene that are mediated by CTCF in normal cultured cells. Using chromosome immunoprecipitation, we found multiple CTCF binding sites on NF1 in cultured cells. We explored long range chromatin associations with each of 7 CTCF binding sites and identified 14 distinct long range interactions. Among the genes that were physically associated with NF1 (which is on chromosome 17) was ARF4 (ADP-ribosylation factor 4, a member of the RAS superfamily involved in membrane traffic, signal transduction and organelle integrity on chromosome 3p14.3. The relative expression of ARF4 was increased several-fold in cells from patients with neurofibromatosis compared to normal cells, suggesting that the interchromosomal interactions of NF1 regulate gene expression on chromosome 3p14.3. It will be of interest to study the potential contribution of these associated genes to the pathophysiology and clinical manifestations of neurofibromatosis 1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2007
- Accession Number
- ADA479323
Entities
People
- Andrew R. Hoffman
Organizations
- Palo Alto Veterans Institute for Research