My research program has focused on the DNA sequences that mediate antibody gene rearrangement events, especially heavy (H) chain class switch recombination. Through examination of the MPCll mouse myeloma cell line and its variants, we have observed another recombination event, not confined to antibody genes, namely, unequal sister chroinatid exchange (USCE). We propose to generate a universal substrate for assaying recombinogenic sequences, including those that mediate H chain class switching and those involved in USCE. The MPCll USCE event involves TC and TG dinucleotide tracts, each of which is capable of adopting an unusual DNA conformation for TC, a triplestranded structure, and for TG, left-handed DNA. We propose to examine the DNA conformation of the juxtaposed TC and TG dinucleotide tracts at the site of the USCE event. We have begun analysis of MPCll variant cells that are apparently and interestingly unstable in that they show rearrangements of both constant and Variable regions, implying some independence from feedback regulation. Initial study of one variant has led to the observation that sequences lying 3' of the Ca gene undergo rearrangements in several myeloma and hybridoma cell lines. We propose experiments to investigate the functional and structural significance of these 3'beta rearrangement events to the organization and expression of the Ig cluster. Our long term goal is to understand how patterned Ig rearrangements may be governed and how promiscuous rearrangements underlying various malignancies may be avoided.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI013509-15
Application #
3480743
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1976-06-30
Project End
1994-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
15
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Frezza, Domenico; Tolusso, Barbara; Giambra, Vincenzo et al. (2012) Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus. Ann Rheum Dis 71:1309-15
Chatterjee, Sanjukta; Ju, Zhongliang; Hassan, Rabih et al. (2011) Dynamic changes in binding of immunoglobulin heavy chain 3' regulatory region to protein factors during class switching. J Biol Chem 286:29303-12
Yan, Yi; Pieretti, Joyce; Ju, Zhongliang et al. (2011) Homologous elements hs3a and hs3b in the 3' regulatory region of the murine immunoglobulin heavy chain (Igh) locus are both dispensable for class-switch recombination. J Biol Chem 286:27123-31
Giambra, Vincenzo; Volpi, Sabrina; Emelyanov, Alexander V et al. (2008) Pax5 and linker histone H1 coordinate DNA methylation and histone modifications in the 3'regulatory region of the immunoglobulin heavy chain locus. Mol Cell Biol 28:6123-33
Ju, Zhongliang; Volpi, Sabrina A; Hassan, Rabih et al. (2007) Evidence for physical interaction between the immunoglobulin heavy chain variable region and the 3'regulatory region. J Biol Chem 282:35169-78
Schweitzer, Brock L; Huang, Kelly J; Kamath, Meghana B et al. (2006) Spi-C has opposing effects to PU.1 on gene expression in progenitor B cells. J Immunol 177:2195-207
Garrett, Francine E; Emelyanov, Alexander V; Sepulveda, Manuel A et al. (2005) Chromatin architecture near a potential 3' end of the igh locus involves modular regulation of histone modifications during B-Cell development and in vivo occupancy at CTCF sites. Mol Cell Biol 25:1511-25
Sepulveda, Manuel A; Emelyanov, Alexander V; Birshtein, Barbara K (2004) NF-kappa B and Oct-2 synergize to activate the human 3' Igh hs4 enhancer in B cells. J Immunol 172:1054-64
Manis, John P; Michaelson, Jennifer S; Birshtein, Barbara K et al. (2003) Elucidation of a downstream boundary of the 3' IgH regulatory region. Mol Immunol 39:753-60
Barlev, Nickolai A; Emelyanov, Alexander V; Castagnino, Paola et al. (2003) A novel human Ada2 homologue functions with Gcn5 or Brg1 to coactivate transcription. Mol Cell Biol 23:6944-57

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