The human genome is made up of two copies of each chromosome that are stored within the nucleus of cells. In addition to their number and structure, the position and spatial dynamics of chromosomes are under tight control. There is abundant evidence that direct interactions between chromosomes can be supported and even contribute to the activation or repression of several genes. My studies will focus on a particular type of interaction, that which occurs between maternal and paternal copies of chromosomes, known as homolog pairing. Many pairing-driven processes are essential for human development and can cause disease when gone awry, with outcomes ranging from cancers to compromised immune systems, physical deformities, and death. While a tremendous amount has been learned about the need of pairing on downstream homology- driven processes, almost nothing is known about how homologous chromosome segments find each other, physically align and then form stable pairing interactions within cells. The primary goal of this proposal is to identify and characterize the factors and mechanisms that mediate homolog pairing (Aims 1 and 2). Taking advantage of the fact that homologous chromosomes are intimately paired along their entire length in Drosophila cells, I will screen for mutations that decrease the fidelity of homolog pairing and then characterize the genetic pathways that are identified. Ultimately, the characterization of the genes underlying homolog pairing will not only shed light on the mechanism of pairing itself, but also the mechanisms of pairing-mediated processes that have implications for human development and disease. The process of homolog pairing is particularly relevant to cancer research, as these interactions can lead to dramatic changes in gene expression and may, therefore, contribute to the formation of some tumors. Striking evidence for this has recently been observed in human cells, wherein the maternal and paternal copies of the q arm of human Chromosome 19 inappropriately pair along its entire length in renal oncocytomas. This study raises the very new and exciting possibility that the state of homolog pairing is directly related to cancer. To better understand the impact of chromosomal interactions in the context of cancer, I will therefore also survey a wide variety of tumor cells for their ability to support homolog pairing (Aim 3). If pairing is observed outside of renal oncocytomas, it will indicate that changes in chromosome positioning, in addition to numerical and structural abnormalities, should be considered as an event associated with tumor formation and a new target for the treatment and prevention of cancer.
The issue of interchromosomal interactions is clearly relevant to public health, as pairing can lead to dramatic changes in transcription and may, therefore, directly contribute to metastasis in the case of some tumors. Indeed, aberrant homolog pairing may increase mitotic crossing over and lead to loss-of- heterozygosity, a process that has long been known to be the underlying cause for many diseases, including cancer. If we observe pairing in transformed cells outside of renal oncocytomas, it may indicate that changes in chromosome positioning, in addition to numerical and structural abnormalities, should be considered as a genomic event associated with tumorigenesis.
|Beliveau, Brian J; Boettiger, Alistair N; AvendaÃ±o, Maier S et al. (2015) Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes. Nat Commun 6:7147|
|Joyce, Eric F; Apostolopoulos, Nicholas; Beliveau, Brian J et al. (2013) Germline progenitors escape the widespread phenomenon of homolog pairing during Drosophila development. PLoS Genet 9:e1004013|
|Joyce, Eric F; Williams, Benjamin R; Xie, Tiao et al. (2012) Identification of genes that promote or antagonize somatic homolog pairing using a high-throughput FISH-based screen. PLoS Genet 8:e1002667|
|Beliveau, Brian J; Joyce, Eric F; Apostolopoulos, Nicholas et al. (2012) Versatile design and synthesis platform for visualizing genomes with Oligopaint FISH probes. Proc Natl Acad Sci U S A 109:21301-6|