The precise regulation of gene expression in the cell is an important task only accomplished by the coordination of multiple molecular pathways. One of these pathways involves the regulation of transcription by chromosome structural components. Aberrant control of chromosome structure is associated with a variety of developmental syndromes, deformities, and the progression of tumors due to the misregulation of genes. Recent evidence has linked chromosome structure to gene expression via the formation of DNA loops that bring enhancers in proximity to promoters during enhancer-loop-mediated transcription. Stem cells represent an ideal cell type to dissect transcriptional regulation due to their unique abilities to differentiate into any cell type of an organism, and alo self-renew. To study the molecular processes regulating transcription of the genome we will employ high-throughput genomic-based technologies and methodologies. The objective of this proposed research is to understand the role of Condensin, a protein complex required for the structural maintenance of chromosomes, in mediating transcription. We will map the distribution of Condensin on the genome and we will identify factors responsible for recruitment and distribution of Condensin. We will examine the pattern of genome-wide occupancy of Condensin with other known members of the transcriptional apparatus and also correlate this pattern with gene expression data. Uncovering the function of chromosome structure in transcription remains a largely unexplored area of research and should be considered essential in fully appreciating the interplay between the various processes that influence gene expression programs in the cell.

Public Health Relevance

The packaging of DNA into chromatin is a highly dynamic and organized process that serves many functions, most important of which is the correct expression of genes. The role that chromosome structure plays in gene regulation is an interesting and active area of study since we are just beginning to link specific chromosome structures to functional processes in the cell;an example of this is the looping of enhancer elements to gene promoters during transcription. Aberrant control of chromosome structure leads to many defects associated with the misregulation of genes including developmental syndromes, and the progression of tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA168263-02
Application #
8462461
Study Section
Special Emphasis Panel (ZRG1-F08-K (20))
Program Officer
Jakowlew, Sonia B
Project Start
2012-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$53,942
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Dowen, Jill M; Young, Richard A (2014) SMC complexes link gene expression and genome architecture. Curr Opin Genet Dev 25:131-7
Dowen, Jill M; Fan, Zi Peng; Hnisz, Denes et al. (2014) Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159:374-87