User:ChrisBrown

Back to Lab Members

Back to Silver Lab

Biographical Info

• 5th year graduate student in Pam Silver's lab.
• Biological and Biomedical Sciences graduate program
• Systems Biology department at the Harvard Medical School
• B.S. degree in Biology from Brandeis University, 2002.
• E-mail: crb2012 at gmail dot com

Graduate Work

Genome-Wide Localization of the Nuclear Transport Machinery Couples Transcriptional Status and Nuclear Organization

• Summary: The association of genes with the nuclear pore complex (NPC) and nuclear transport factors has been implicated in transcriptional regulation. We therefore examined the association of components of the nuclear transport machinery including karyopherins, nucleoporins, and the Ran guanine-nucleotide exchange factor (RanGEF) with the Saccharomyces cerevisiae genome. We find that most nucleoporins and karyopherins preferentially associate with a subset of highly transcribed genes and with genes that possess Rap1 binding sites whereas the RanGEF preferentially associates with transcriptionally inactive genes. Consistent with coupling of transcription to the nuclear pore, we show that transcriptional activation of the GAL genes results in their association with nuclear pore proteins, relocation to the nuclear periphery, and loss of RanGEF association. Taken together, these results indicate that the organization of the genome is coupled via transcriptional state to the nuclear transport machinery.

Developmentally Induced Changes in Transcriptional Program Alter Spatial Organization Across Chromosomes

• Summary: Although the spatial location of genes within the nucleus has been implicated in their transcriptional status, little is known about the dynamics of gene location that accompany large-scale changes in gene expression. The mating of haploid yeast Saccharomyces cerevisiae is accompanied by a large-scale change in transcription and developmental program. We examined changes in nuclear organization that accompany stimulus by the mating pheromone alpha factor and found that most alpha factor-induced genes become associated with components of the nuclear envelope. The myosin-like protein Mlp1, which has been implicated in mRNA export, was further shown to exhibit RNA dependence in its association with alpha factor-induced genes. High-resolution mapping of association of chromosome III with Mlp1 revealed alpha factor-dependent determinants of nuclear pore association, including origins of replication, specific intergenic regions, and the 3' ends of transcriptionally activated genes. Taken together, these results reveal RNA- and DNA-dependent determinants of nuclear organization as well as a detailed picture of how an entire chromosome alters its spatial conformation in response to a developmental cue.

FIG2 Locus in Wild Type Cells

FIG2 Locus in Alpha Factor-Induced Cells

Interactions Between the Mammalian Nuclear Pore Complex and the Genome

• Summary: While interactions between the yeast NPC and the genome have been extensively characterized by our lab and several other groups, the existence of such interactions in higher eukaryotes has yet to be investigated. We studied these connections by performing ChIP-chip analysis on mammalian NPC components and discovered numerous NPC-genomic associations. These interactions are significantly altered upon treating cells with drugs and appear to represent a genome-wide reorganization event.

FISH/IF of a Dynamic Loci in HeLa Cells

Publications

• Brown, C.R. and Silver, P.A. Transcriptional regulation at the nuclear pore complex. Curr. Opin. Genet. Dev. 2007. April;17(2):100-6. URL
• Tsankov, A.M., Brown, C.R., Yu, M.C., Win, M.Z., Silver, P.A., and Casolari, J.M. Communication between levels of trancriptional control improves robustness and adaptivity. Mol. Sys. Biol. EPub November 28, 2006. URL
• Brown, C.R. and Silver, P.A. Pore-ing the right dose. Nat. Cell Biol. 2006. May;8(5):430-1. URL
• Auld, K.L., Brown, C.R., Casolari, J.M., Komili, S., and Silver, P.A. Genomic association of the proteasome demonstrates overlapping gene regulatory activity with transcription factor substrates. Mol. Cell. 2006. Mar 17;21(6):861-71. URL
• Casolari, J.M.*, Brown, C.R.*, Drubin, D.A., Rando, O.J., and Silver, P.A. Developmentally induced changes in transcriptional program alter spatial organization across chromosomes. Genes Dev. 2005. May 15;19(10):1188-98. URL
• Beaulieu, V., Da Silva, N., Pastor-Soler, N., Brown, C.R., Smith, P.J., Brown, D., and Breton, S. Modulation of the actin cytoskeleton via gelsolin regulates vacuolar H+-ATPase recycling. J. Biol. Chem. 2005. March 4; 280(9):8452-8463. URL
• Casolari, J.M., Brown, C.R., Komili, S., West, J., Hieronymus, H., and Silver, P.A. Genome-wide localization of the nuclear transport machinery reveals coupling of transcriptional status and nuclear organization. Cell. 2004. May 14; 117(4):427-39. URL

Hobbies

Soccer, squash, volleyball, skiing, and playing the tuba.