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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM080484-06A1
Application #
8504306
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Carter, Anthony D
Project Start
2007-08-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$290,828
Indirect Cost
$95,828
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Sood, Varun; Brickner, Jason H (2014) Nuclear pore interactions with the genome. Curr Opin Genet Dev 25:43-9
D'Urso, Agustina; Brickner, Jason H (2014) Mechanisms of epigenetic memory. Trends Genet 30:230-6
Egecioglu, Defne Emel; D'Urso, Agustina; Brickner, Donna Garvey et al. (2014) Approaches to studying subnuclear organization and gene-nuclear pore interactions. Methods Cell Biol 122:463-85
Light, William H; Freaney, Jonathan; Sood, Varun et al. (2013) A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory. PLoS Biol 11:e1001524
Meldi, Lauren; Brickner, Jason H (2011) Compartmentalization of the nucleus. Trends Cell Biol 21:701-8
Brickner, Donna Garvey; Brickner, Jason H (2011) Gene positioning is regulated by phosphorylation of the nuclear pore complex by Cdk1. Cell Cycle 10:392-5
Leung, Amy; Cajigas, Ivelisse; Jia, Peilin et al. (2011) Histone H2B ubiquitylation and H3 lysine 4 methylation prevent ectopic silencing of euchromatic loci important for the cellular response to heat. Mol Biol Cell 22:2741-53
Egecioglu, Defne; Brickner, Jason H (2011) Gene positioning and expression. Curr Opin Cell Biol 23:338-45
Light, William H; Brickner, Donna G; Brand, Veronica R et al. (2010) Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. Mol Cell 40:112-25
Ahmed, Sara; Brickner, Donna G; Light, William H et al. (2010) DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery. Nat Cell Biol 12:111-8

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