5 U01 U01HG04270
Identification of DNA Elements Governing Chromatin Funct
| Principal Investigator: |
JASON LIEB
UNIV OF NORTH CAROLINA
BIO & CAROLINA CTR FOR GEN SCIS
203 FORDHAM HALL, CB#3280
THE UNIV. OF NC AT CHAPEL HILL
|
Project Period: 05/04/2007 - 03/31/2011
Abstract (from grant application):
DESCRIPTION (provided by applicant): Eukaryotic genomes are packaged into chromatin, which regulates the function of proteins that mediate transcriptional activity and other essential processes, including recombination and the faithful segregation of the genome during mitosis and meiosis. The goal of this proposal is to identify discrete elements that regulate chromatin structure and function in the nematode C. elegans, a model metazoan of central importance in large-scale genomic research and gene function discovery. We will first use ChlP-chip and related methods to map the genomic distributions of selected histone modifications and chromosome-associated proteins, and then use that information, in combination with data from other modENCODE groups, to build quantitative models of chromatin function. Specifically, we will: 1. Identify and technically validate functional elements that control chromatin and chromosome behavior. The focus of our analysis will be elements that specify nucleosome positioning and occupancy, control domains of gene expression, induce repression of the X chromosome, guide mitotic segregation and genome duplication, govern homolog pairing and recombination during meiosis, and organize chromosome positioning within the nucleus. 126 strategically selected targets include key histone modifications, histone variants, RNA polymerase II isoforms, dosage-compensation proteins, centromere components, homolog-pairing facilitators, recombination markers, and nuclear-envelope constituents. An efficient pipeline design will facilitate identification and validation of the different classes of functional elements associated with these targets and will integrate the results with the well-annotated C. elegans genome. 2. Biologically validate identified functional elements and build integrated, quantitative models of chromosome function. We will integrate information generated in Aim 1 with existing knowledge on the biology of the targets, perform ChlP-chip analysis on mutant and RNAi extracts lacking selected target proteins, use extrachromosomal arrays to assess the ability of candidate identified sequence motifs to recruit targets in vivo, identify tissue-specific patterns of selected targets, and create integrated, quantitative models of transcription and whole-chromosome functions. Achieving these goals in the context of the ongoing expansion and rich history of C. elegans research will provide an important milestone in meeting the challenge of using genome sequence information to understand and predict biological functions.
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