Barbara Birshtein, PhD

Professor, Department of Cell Biology Chanin Bldg., Room 417 718 430-2291 birshtei@aecom.yu.edu Biosketch Complete list of publications Laboratory Web Site

Research interests Regulation of Antibody Heavy Chain Gene Rearrangements and Expression The immune system is our spacesuit for life in an environment containing enormous numbers of infectious agents. An essential part of the immune system is the B cell, which is the only cell type that produces antibodies. Antibody (Ig) genes are constructed via a series of DNA rearrangements. Occasionally, mistakes occur during antibody construction, which activate oncogenes and lead to cancers. My long term goal is to understand the mechanisms that initiate and control antibody gene rearrangements. Our experiments focus on a complex 3' Igh regulatory region that lies immediately downstream of the antibody heavy chain gene cluster in mouse and humans. This ~50 kb "ignition" region contains several B cell-specific enhancers and newly described additional putative regulators. 3?enhancers are essential for the DNA rearrangements that lead to the expression of different classes of antibodies (class switch recombination). The 3?regulatory region is also likely to regulate high levels of expression of antibodies in fully differentiated plasma cells and perhaps contribute to somatic hypermutation. We propose that the newly identified sequences insulate the heavy chain locus from its nearest non-Igh gene neighbors. A major goal of our laboratory is to understand the mechanisms by which 3?regulators function in both mouse and human. In collaborative studies, we have identified changes in replication of antibody heavy chain genes during B cell differentiation, raising the exciting possibility that mechanisms of replication are coordinated with antibody gene rearrangements and expression. The extended 3' Igh regulatory region may provide multiple boundaries for DNA replication and rearrangement events. We are interested in identifying the extent of B cell-specific regulation of the Igh locus, by analyzing chromatin changes in 3' Igh sequences during B cell development and class switching. We are also identifying B-cell specific “keys?-trans-acting nuclear DNA-binding proteins that regulate 3' Igh sequences, including 3' Igh enhancers. Of particular focus is Pax5/BSAP, a transcription factor that is essential for B cell development. Our experiments show that Pax5 acts as a negative regulator to repress one of 3' Igh enhancers, and as a positive activator of a key intermediate in production of the allergic antibody, IgE. We are examining the role of Pax5's protein partners in helping Pax5 to function in transcription and B cell development. In recent collaborative studies, we have shown that Pax5 has the potential to coordinate multiprotein complexes involved in chromatin remodeling and histone acetylation.

Recent publications Saleque, S., Singh, M., Little, R.D., Giannini, S.L., Michaelson, J.S., and Birshtein, B.K. (1997) "Dyad Symmetry Within the Mouse 3' IgH Regulatory Region Includes Two Virtually Identical Enhancers (Cα3'E and hs3)". J. Immunol. 158: 4780-4787. Saleque, S., Singh, M. and Birshtein, B. K., (1998) "IgH Expression and Class Switching in Vitro from an Allele Lacking the 3' Enhancers HS3A and HS1,2. J Immunol. 1999 Mar 1;162(5):2791-803. Ermakova, O. V, Nguyen, Lam H., Little, R. D., Chevillard, C., Riblet, R., Ashouian, N., Birshtein, B. K. and Schildkraut, C. L. (1999) "Evidence that the Transition between Early and Late Replicating Domains of the Immunoglobulin Heavy Chain Gene Locus in a Non B Cell Line is Accomplished by a Single Replication Fork". Mol Cell. 1999 Mar;3(3):321-30.   Kovac, C.R., Emelyanov, A., Singh, M., Ashouian, N. and Birshtein, B.K. (2000) BSAP (Paх5)-Importin a1 (Rch1) Interaction Identifies a Nuclear Localization Sequence. J Biol Chem 2000 Jun 2;275(22):16752-7 Emelyanov, A., Kovac, C.R., Sepulveda, M.A., and Birshtein, B.K., (2002) “The Interaction of Pax5 (BSAP) with Daxx Can Result in Transcriptional Activation in B Cells? J Biol Chem 2002 277:11156-11164  Zhou, Jie, Ermakova, O. V., Riblet, R., Birshtein, B. K., and Schildkraut, C. L. (2002) “Replication and Subnuclear Location Dynamics of the Immunoglobulin Heavy-Chain Locus in B Lineage Cells? Mol. Cell. Biol. 22:4876-4889.  Zhou, J.*, Ashouian, N.*, Delepine, M., Matsuda, F., Chevillard, C., Riblet, R., Schildkraut, C.L., and Birshtein, B.K. (2002) “The origin of a developmental regulated IgH replicon is located near the border of regulatory domains for IgH replication and expression. *Co-first authors. Proc. Natl. Acad. Sci. USA, 99:13693-13698.  Manis, J. P., Michaelson, J. S., Birshtein, B, K., and Alt, F, W. (2003) “Elucidation of a downstream boundary of the 3?IgH regulatory region? Mol. Immunol. 39:753-760.  Gordon, S. J., Saleque, S. and Birshtein, B. K. (2003) Yin Yang 1 (YY1) is an LPS-inducible activator of the murine 3' Igh enhancer, hs3". J. Immunol., 170:5549-5557.  Barlev, N. A.,* Emelyanov, A. V.,* Castagnino, P., Zegerman, P., Bannister, A., Sepulveda, M. A., Kouzarides, T., Birshtein, B. K., and Berger, S. L. (2003) "A novel human Ada2 homologue functions with Gcn5 or Brg1 to coactivate transcription." *Co-first authors. Mol. Cell. Biol. 23:6944-6957. Sepulveda, M.A,, Emelyanov, A. V., and Birshtein, B. K. (2004) “NF-kB and Oct-2 synergize to activate the human 3?Igh hs4 enhancer in B cells.?J. Immunol. 172:1054-1064.

Barbara Birshtein: Research interests | Biosketch Faculty research at a glance Birshtein | Bouhassira | Edelmann | Fyodorov | Keogh | Kielian | Kitsis | Nathenson | Query Scharff | Schildkraut | Shafritz | Singer | Skoultchi | Stanley | Steidl |Warner | Ye   Home