Interchromosomal Associations that Alter NF1 Gene Expression Can Modify Clinical Manifestations of Neurofibromatosis 1

摘要

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 and in cells derived from patients with neurofibromatosis. 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 in cells and tissues from patients with neurofibromatosis compared to normal cells, suggesting that the interchromosomal interactions of NF1 regulate gene expression on chromosome 3p14.3.4. Data obtained this year suggests that ARF4 might play a role in neurofibromatosis 1 tumorigenesis. The search for novel remote gene interactions with NF1 promises to open up totally new ranges of therapeutic targets.