Transcriptional Programming in normal and malignant B-cells

Rationale:

B-cells undergo dramatic phenotypic shifts during their normal maturation process and in response to antigen stimulation. T-cell dependent antigen responses induce B-cell activation and cause a subset of B-cells to form germinal centers within which they undergo clonal expansion, somatic hypermutation and class switch recombination. A majority of B-cell neoplasms arise from germinal center B-cells or from cells that have undergone the germinal center reaction. Because of this we are particularly interested in the biochemical and biological mechanism of action of transcription factors that impose the germinal center phenotype, since many of these are also expressed in lymphoma cells and may contribute to lymphomagenesis. A major focus for the lab in recent years is the BCL6 transcriptional repressor, however several other factors are under investigation. The overall goal is to determine how these different transcription factors function from the biochemical standpoint and how they interact to form a network of interactions throughout the genome that results in the phenotypic features of the different compartments of B-cells.

Goals:

To identify the composition of transcriptional complexes formed by BCL6 and other B-cell transcription factors
To determine the impact of these factors on chromatin and how chromatin configuration contributes to the cellular phenotype
To identify the target genes regulated by BCL6 and other B-cell transcription factors and how they contribute to the biological effect of these proteins
To determine how B-cell transcription factors can initiate and maintain the lymphomagenic phenotype


Projects:

Identification of BCL6 transcriptional complexes and their effects on chromatin
Identification of BCL6 target genes and their contribution to the BCL6 mediated phenotype in normal vs. malignant cells
Identification of B-cell transcription factor biochemical mechanisms of action, transcriptional targets and biological actions

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