Role of TFII-I in B cell function

Roy, Ananda

Abstract

The antibody producing B-lymphocytes are generated throughout the life of most mammals and are essential for immune function. The functional B-lymphocytes are generated via differentiation of precursor B cells, which requires signaling via the B cell receptor (BCR) both during antigen independent and antigen dependent phases of development. Each step of differentiation is also characterized by epigenetic changes and expression patterns of a specific set of genes. However, the mechanism by which BCR signaling is connected to epigenetic changes in downstream target genes and alterations in their transcription during B cell activation is unknown. The multifunctional transcription factor TFII-I is activated upon BCR signaling and undergoes regulated translocation from the cytoplasm to the nucleus. TFII-I also interacts with various chromatin factors and regulates target genes including the immunoglobulin heavy chain, IgH. We hypothesize that by virtue of association with both general chromatin factors and cell type specific transcription factors in response to BCR-signaling, TFII-I connects BCR signaling to chromatin architecture and transcription of Ig and non-Ig genes. In addition, TFII-I intersects with the NF-B pathway. We propose that these interactions are functionally important for B cell proliferation. Because deregulation in signaling or gene expression in B cells can lead to various malignancies and immune deficiencies, it is our long-term goal to dissect in molecular detail the TFII-I mediated pathways operating in B cells. To investigate the BCR-mediated transcriptional and proliferative mechanisms in B cells, we propose the following specific aims: 1) To ascertain how TFII-I mediates BCR signaling via Btk and activates target genes; 2) To determine the role of TFII-I in IgH transcriptional regulation; 3) To elucidate the mechanism by which TFII-I intersects with the NF-B pathway

Public Health Relevance

The generation of differentiated cell types, from their corresponding undifferentiated precursors, is regulated by signals emerging from the cell extrinsic environment and the ability of the recipient cell to transduce these signals to effect changes in their gene expression patterns. Despite years of study, significant questions remain unanswered about how specific signals control genes responsible for immune function. TFII-I is a transcription factor that controls expression of the immunoglobulin gene in antibody producing B cells. We propose to study how this factor integrates external signals to control antibody production and thus, modulate immune function.