We used to think of genes as discrete segments of DNA that code for proteins and that are regulated or controlled by nearby or adjacent DNA sequences. Recently, it has been shown that DNA sequences on the same chromosome that are very distant from a gene may regulate its function, determining if the gene will be turned on or turned off. We have now discovered that DNA sequences that are even on different chromosomes from the protein-coding gene may control this gene. These interactions are often totally unexpected. For example, the NF1 gene, which causes neurofibromatosis, a genetic disease that may lead to the development of brain tumors, lies on chromosome 11 in the mouse, but the production of its protein product is partially under the control of a DNA segment near a growth factor gene(IGF2) on mouse chromosome 7; the same relationship appears to hold true in humans. No one had ever suspected such an interaction, and it is now logical to consider targeting the IGF2 gene as part of our hopes to treat neurofibromatosis. In other words, the discovery of a long-range interacting sequence of DNA provides us with totally new targets for drug development.
Several other groups have also shown that inter-chromosomal gene regulation can control immune genes and the genes that regulate our sense of smell. We believe that many, if not most, genes are controlled, as least in part, by long range inter-chromosomal interactions, and we have proposed a new method to try to define all of these interactions in cultured human cells. It is highly likely that many of these long range inter-chromosomal interactions are important in the regulation of a gene, and therefore, we plan to catalog all of these interactions in human embryonic stem cells, and see whether the interactions remain the same or are altered as the cells differentiate into fat cells, and, in the future, into other kinds of cells. This catalog will provide us with numerous new clues to the regulation of disease-related genes, and will suggest new drug or gene-therapy related targets to treat these diseases. By comparing the list of interacting genes in normal embryonic cells with those in cells harboring a genetic disease, we may develop new diagnostic tools in addition to potential therapeutic avenues.
Statement of Benefit to California:
Our goal is to characterize how genes are regulated by distant DNA segments on different chromosomes. We will develop a complete catalog of these long range interactions, which will provide a list of how one gene may regulate another. This catalog will provide the framework for determining how disease-related genes are controlled and will allow investigators to develop new diagnostic tools and/or new therapeutic targets to treat various genetic diseases. These are targets that had never heretofore been considered because the long range interactions among these genes had not been known. Clinical translation of these studies into new drugs will be of great benefit to the people of California.