Normal processes of cellular differentiation involve coordinated programs of tissue-specific gene expression. Recently, genome-wide approaches to mapping histone modification and transcription factor binding patterns have revealed that promoter-distal enhancer sequences exhibit the greatest variability among distinct mammalian cell types, and that they most likely represent the most significant determinant of tissue-specific gene expression. Using erythroid differentiation as a model system, we have previously investigated the phenomenon of hyperacetylated domains, which consist of broadly-distributed (>12 kb) patterns of histone modifications that are usually confined solely to the promoter-proximal regions of active genes, and we have accumulated evidence that such domains represent a function of a specific class of distal enhancer element. We are therefore interested in investigating the mechanism by which such enhancers mediate domain formation, in order to gain insight into how hyperacetylated domains contribute to tissue-specific gene activation during terminal differentiation. To do this, we will investigate candidate erythroid-specific domain-forming enhancers in detail to identify the DNA-binding factors required for their activity, and in turn the associated cofactors and histone modifying enzymes. In addition, we will define the requirements for domain formation at a gene locus active in both erythroid and liver cells, and thus determine the features common between domains in different cell types. From these studies, we hope to elucidate the specific mechanisms by which distal enhancers mediate erythroid-specific gene activation during erythroid maturation.

Public Health Relevance

Our goal is to understand how regulatory DNA sequences contribute to the program of gene expression that characterizes the process of differentiation that leads to the production of red blood cells. Such sequences, termed enhancers, are a crucial determinant of normal gene expression patterns, and in turn are targets for mutations that can lead to disease. Moreover, an understanding of enhancer function will ultimately contribute to the successful development of transgene therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK070687-06A1
Application #
8503788
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2005-04-01
Project End
2017-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$227,040
Indirect Cost
$77,040
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Cadiz-Rivera, Brenda; Fromm, George; de Vries, Christina et al. (2014) The chromatin "landscape" of a murine adult ?-globin gene is unaffected by deletion of either the gene promoter or a downstream enhancer. PLoS One 9:e92947
Bulger, Michael; Groudine, Mark (2011) Functional and mechanistic diversity of distal transcription enhancers. Cell 144:327-39
Fromm, George; Cadiz-Rivera, Brenda; de Vries, Christina et al. (2011) An embryonic stage-specific enhancer within the murine *-globin locus mediates domain-wide histone hyperacetylation. Blood 117:5207-14
Fromm, George; de Vries, Christina; Byron, Rachel et al. (2009) Histone hyperacetylation within the beta-globin locus is context-dependent and precedes high-level gene expression. Blood 114:3479-88