EZH2 is the histone methyltransferase component of the polycomb repressor complex 2 (PRC2), which is required for repression of numerous lineage specifying transcription factors during development. Recent studies have revealed that both gain and loss of function of EZH2 can contribute to lymphoid malignancy. Here we will test the hypothesis that EZH2 is required for commitment of common lymphoid progenitors to the adaptive lymphocyte (B and T cell) fates but not to innate lymphocyte (ILC1 and ILC2) fates. We will test this hypothesis by examining the consequences of Ezh2 inactivation in common lymphoid progenitors under competitive and non-competitive conditions by flow cytometric analysis of lymphoid cells and through the use of in vitro assays that measure both frequency of differentiation and commitment to a given lineage. In parallel we will identify EZH2 target genes by examining the global changes in gene expression in lymphocytes and their progenitors caused by EZH2-deficiency as well as identifying genes that are bound by EZH2 and fail to undergo H3K27 trimethylation, the hallmark of EZH2 activity, in EZH2-deficient cells. Taken together, our study will provide significant insight into the mechanisms controlling gene expression during lymphocyte lineage specification and commitment. In addition, we will gain a better understanding of how EZH2 mutations lead to leukemia and lymphoma and how treatment of these diseases with EZH2 inhibitors might influence normal lymphocyte development.

Public Health Relevance

Adaptive and innate lymphoid cells develop from a common progenitor but the mechanisms controlling specification and commitment to these lineages are largely unknown. Using mice with a conditional deletion of Ezh2 in common lymphoid progenitors we will test the hypothesis that EZH2 is required for adaptive but not innate lymphoid lineage commitment while simultaneously identifying targets of this histone methyltransferase.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI109233-01
Application #
8622415
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Nasseri, M Faraz
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$177,750
Indirect Cost
$65,250
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637