The long term goal of our work is to understand the molecular mechanisms through which different chromosomes physically interact. In this proposal we focus specifically on how trans-interactions are negatively regulated. Chromosomal trans-interactions have been seen in somatic cells and meiotic cells of many species, including human. A current view of chromosome trans-interactions posits that proteins bring chromosomes into intimate proximity and allow coordination of gene expression or chromosome segregation. For example, chromosome trans-interactions are important for gene activation in the mouse olfactory receptor gene and the mouse TH2 LCR locus. A variety of trans-interactions also have been observed in Drosophila, both in somatic cells (e.g.transvection, trans-silencing, polytene chromosomes) and in meiotic cells where extensive interactions pair homologous chromosomes throughout their lengths. Meiotic pairing is important for proper chromosome segregation and for epigenetic processes such as X-inactivation, imprinting, and pairing-sensitive meiotic gene silencing in mammals, plants and fungi. Both somatic and meiotic pairing can occur by mechanisms that are completely independent of DNA recombination and repair proteins. How chromosomes pair and unpair is largely unknown in any organism. Although a handful of proteins have been described to mediate recombination independent meiotic pairing, there is nothing known about what regulates somatic chromosome pairing. It is not known whether somatic and meiotic chromosome pairing are structurally similar or if they are regulated by the same factors. Work from my laboratory has recently demonstrated that pairing of somatic diploid chromosomes, polytene chromosome pairing and meiotic chromosome pairing are all antagonized by the condensin II complex. How condensins do this is unclear. However, our observations provide the first molecular insight into a somatic pairing mechanism, and we demonstrate a novel chromosome anti-pairing function for condensins. Condensins are conserved from bacteria to humans, therefore understanding how they regulate chromosome interactions will reveal basic functions likely to be important in all species. This proposal builds on our recent work on condensin. First, we will use genetics to identify the proteins that cooperate with condensins to regulate polytene chromosome unpairing. Second, we will determine the mechanism(s) through which condensins regulate chromosome pairing sensitive gene expression in diploid somatic cells. Third, we will determine the function of condensins, and their interacting proteins, in regulating meiotic chromosome pairing.
We seek to understand the molecular mechanisms through which different chromosomes physically interact. In this proposal we focus specifically on how trans- interactions are negatively regulated by a set of multi-protein complexes known as condensins. Chromosome interactions leading to pairing of homologous sequences is important for gene regulation and chromosome segregation in meiosis. We propose experiments that will determine the molecular function of condensins as chromosome anti-pairing factors. The experiments proposed in this grant application will have a direct and significant impact on the advancement of biomedical research and human health.
|Nguyen, Huy Q; Bosco, Giovanni (2015) Gene Positioning Effects on Expression in Eukaryotes. Annu Rev Genet 49:627-46|
|Wallace, Heather A; Klebba, Joseph E; Kusch, Thomas et al. (2015) Condensin II Regulates Interphase Chromatin Organization Through the Mrg-Binding Motif of Cap-H2. G3 (Bethesda) 5:803-17|
|Nguyen, Huy Q; Nye, Jonathan; Buster, Daniel W et al. (2015) Drosophila casein kinase I alpha regulates homolog pairing and genome organization by modulating condensin II subunit Cap-H2 levels. PLoS Genet 11:e1005014|
|Bozler, Julianna; Nguyen, Huy Q; Rogers, Gregory C et al. (2015) Condensins exert force on chromatin-nuclear envelope tethers to mediate nucleoplasmic reticulum formation in Drosophila melanogaster. G3 (Bethesda) 5:341-52|
|Li, Li; Lyu, Xiaowen; Hou, Chunhui et al. (2015) Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing. Mol Cell 58:216-31|
|Wallace, Heather A; Merkle, Julie A; Yu, Michael C et al. (2014) TRIP/NOPO E3 ubiquitin ligase promotes ubiquitylation of DNA polymerase Î·. Development 141:1332-41|
|George, Carolyn M; Bozler, Julianna; Nguyen, Huy Q et al. (2014) Condensins are Required for Maintenance of Nuclear Architecture. Cells 3:865-82|
|Buster, Daniel W; Daniel, Scott G; Nguyen, Huy Q et al. (2013) SCFSlimb ubiquitin ligase suppresses condensin II-mediated nuclear reorganization by degrading Cap-H2. J Cell Biol 201:49-63|
|Peterson, Maureen; Chandler, Vicki L; Bosco, Giovanni (2013) High SINE RNA Expression Correlates with Post-Transcriptional Downregulation of BRCA1. Genes (Basel) 4:226-43|
|Wallace, Heather A; Bosco, Giovanni (2013) Condensins and 3D Organization of the Interphase Nucleus. Curr Genet Med Rep 1:219-229|
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