A fundamental property of differentiated cells is that they utilize a unique combination of gene products, some that are ubiquitously expressed and others that are cell type specific. We have identified several lineage restricting elements in the promoter regions of the CD19 and CD20 genes that help to confer B-lymphocyte specific expression, as well as several elements that bind ubiquitously expressed transcription factors. One key regulatory element binds the B-cell specific activator protein (BSAP). The development of antibodies against BSAP allowed the identification of a BSAP variant of smaller molecular mass that has an alternative COOH terminus. This product is expressed in pre-B cell lines, localizes in the cytoplasm, and shifts to the nucleus following activation. We have also found that BSAP is regulated during B-cell differentiation within the germinal center regions of lymph nodes and we have established a set of BSAP transgenic mice to examine the consequences of forced over-expression of BSAP in B cells. We have also found that BSAP is markedly over-expressed in certain high grade B-cell lymphomas. To evaluate the mechanisms regulating BSAP gene transcription in normal B cells and B-cell lymphomas, we isolated the BSAP promoter region and identified several in vivo footprinted regions in the promoter. However, promoter-constructs have not behaved as expected suggesting the presence of a potent negative regulatory element. Another approach to analyze the role of transcription factors in vivo is to create mice deficient in a specific transcription factor (""""""""knock-out"""""""" mice). HB9 is a homeobox gene present at high levels in a subset of B cells in humans. We have targeted the HB9 gene in mice. The HB9 +/- mice are apparently normal, however, the HB9 -/- mice die at birth perhaps because of a problem with motor neuron development. Analysis of hematopoiesis in these mice is in progress. Overall, these studies are leading to a better understanding of the complex interplay between transcription factors and their target sequences in generating lineage specific gene expression.
| Thaler, J; Harrison, K; Sharma, K et al. (1999) Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron 23:675-87 |
| Harrison, K A; Thaler, J; Pfaff, S L et al. (1999) Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet 23:71-5 |
