Gene expression is regulated by transcription factors, chromatin structure and higher order organization. The positioning of genes within the nucleus and with respect to each other often correlates with their expression. However, the molecular mechanisms that control gene positioning within the nucleus, and the functional significance of gene positioning, are unclear. As a model to understand gene positioning, we have focused on the molecular mechanisms by which genes move from the nucleoplasm to the nuclear periphery upon activation in Saccharomyces cerevisiae. Targeting to the nuclear periphery involves a physical interaction with the nuclear pore complex (NPC) and is mediated by cis-acting Gene Recruitment Sequences (GRSs). GRSs function as DNA zip codes: they are necessary and sufficient to induce interaction with the NPC and localization at the nuclear periphery. Furthermore, zip codes confer interchromosomal clustering of genes at the nuclear periphery. This suggests that the yeast genome encodes its spatial organization and that cis-acting DNA sequences control interchromosomal clustering of genes through interaction with the NPC. We have identified several DNA zip codes and a protein that recognizes the GRS I zip code to mediate targeting to the nuclear periphery and interchromosomal clustering. The proposed studies will 1) determine the molecular mechanism by which the GRS I DNA zip code mediates targeting to the nuclear periphery and promotes transcription, 2) determine the genome-wide scope of GRS I zip code-mediated targeting and 3) test the hypothesis that DNA zip codes impact the global organization of the yeast genome.

Public Health Relevance

Like the rest of the cell, the nucleus is spatially organized;chromosomes fold and occupy non- random positions and the position of individual genes impacts their expression. My lab has discovered that the position of genes is controlled by DNA zip codes. This proposal seeks to define the molecular mechanism by which zip codes control gene positioning and expression and to test the role of zip codes in controlling the spatial organization of the genome.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Carter, Anthony D
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Sood, Varun; Cajigas, Ivelisse; D'Urso, Agustina et al. (2017) Epigenetic Transcriptional Memory of GAL Genes Depends on Growth in Glucose and the Tup1 Transcription Factor in Saccharomyces cerevisiae. Genetics 206:1895-1907
Brickner, Jason (2017) Genetic and epigenetic control of the spatial organization of the genome. Mol Biol Cell 28:364-369
D'Urso, Agustina; Brickner, Jason H (2017) Memory Is the Treasury and Guardian of All Things. Mol Cell 66:5-6
D'Urso, Agustina; Brickner, Jason H (2017) Epigenetic transcriptional memory. Curr Genet 63:435-439
Sump, Bethany; Brickner, Jason H (2017) Nup98 regulation of histone methylation promotes normal gene expression and may drive leukemogenesis. Genes Dev 31:2201-2203
Kim, Seungsoo; Liachko, Ivan; Brickner, Donna G et al. (2017) The dynamic three-dimensional organization of the diploid yeast genome. Elife 6:
Satomura, Atsushi; Brickner, Jason H (2017) Nuclear Pore Complexes: A Scaffold Regulating Developmental Transcription? Trends Cell Biol 27:621-622
Brickner, Donna Garvey; Sood, Varun; Tutucci, Evelina et al. (2016) Subnuclear positioning and interchromosomal clustering of the GAL1-10 locus are controlled by separable, interdependent mechanisms. Mol Biol Cell 27:2980-93
Randise-Hinchliff, Carlo; Brickner, Jason H (2016) Transcription factors dynamically control the spatial organization of the yeast genome. Nucleus 7:369-74
D'Urso, Agustina; Takahashi, Yoh-Hei; Xiong, Bin et al. (2016) Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory. Elife 5:

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