Genomic studies of motif enrichment and conservation in the regulation of gene expression in the brain

Several bioinformatic tools will be brought to bear in this thesis to identify specific genomic loci that serve as regulatory gateways of gene expression in brain. These "motifs" are short nucleotide patterns that occur in promoters and 5' or 3' untranslated regions of genes. Occurrences of motifs that function in eukaryotic genomes as, e.g., transcription factor binding sites or targets of RNA interference are assumed to lie at the nexus of several trends. Instances that are indeed regulatory and not just bits of random sequence should show evidence of actual binding of factors that have a significant effect on expression levels. Such motif instances are also expected to be significantly enriched (or de-enriched), compared to background, in the genes regulated by their binding factors and in brain structures most closely associated with these genes' functions. Finally, truly regulatory motif instances are likely to be highly conserved in orthologous genes across multiple genomes; i.e., conservation can be taken as a proxy for function. My research exploits these ideas by exploring genome-wide properties of motifs associated with the transcription factor family MEF2, some of whose members are known to play a role in synapse development. Data from chromatin immunoprecipitation and tiling-microarray (ChIP-on-chip) experiments [11 have isolated peaks of specific binding by MEF2 in developing rat brains. Conservation and enrichment of these sites are analyzed here for their association with functionality and variability of motifs in genes that have been shown to fall under the control of MEF2 in excitatory neurons.

Department dc:contributor.department

Harvard University--MIT Division of Health Sciences and Technology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2008

Author dc:creator

• Harmin, David Alan, 1954-

Advisor dc:contributor.advisor

• Isaac S. Kohane.

• Harvard University--MIT Division of Health Sciences and Technology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/43811

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/43811