The Atchison laboratory is interested in determining the molecular mechanisms responsible for transcriptional regulation and the control of B cell development. To pursue these studies, we explore the functions of a number of transcription factors that regulate immunoglobulin gene expression and that play important roles in immunoglobulin locus structure, antibody maturation, lineage differentiation, and oncogenesis. We pursue our studies by biochemical, molecular biological, genetic, and developmental approaches using a variety of experimental systems including cell lines representing defined stages of B cell development, multipotential tumor lines, transgenic animals, and chimeric mice. General areas of current interest include:
1. Developmental control of immunogloblulin locus structure. Transcription factor YY1 is crucial for B cell development, and we found this factor can regulate immunoglobulin kappa V gene rearrangement and repertoire. Current data suggest that YY1 binds to numerous locations within the kappa locus and associates there with Polycomb Group, Condensin, and Cohesin proteins. We speculate that YY1 nucleates the binding of these factors to the kappa locus in a tissue-specific and developmental stage-specific fashion.
2. Mechanism of antibody maturation. Within germinal center cells antibody genes undergo somatic maturation processes involving class switch recombination and somatic hypermutation. Both of these processes require the enzyme, Activation Induced Deaminase (AID). Levels of AID in the nucleus are very tightly regulated and misregulation of AID leads to B cell lymphoma. We found that transcription factor YY1 can physically interact with AID leading to increased nuclear stability and increased class switch recombination. We are currently studying the mechanism of this stabilization, and the role of YY1-AID interaction in B cell lymphoma.
3. Function of the transcription factor YY1 as a Polycomb-Group protein in transcriptional repression and embryonic development. We found that human YY1 can function as a Polycomb protein in vivo to repress transcription and to control embryonic development. YY1 also recruits other PcG proteins to DNA resulting in specific histone post-translational modifications. We are studying the mechanism of this recruitment and specific proteins that bridge YY1 to the Polycomb Group complex repressor proteins.
4. Function of YY1 in B cell lymphomagenesis. Physical interaction of YY1 with AID may augment its role in germinal center derived B cell lymphomagenesis. We are using mice that spontaneously develop B cell lymphoma to determine the impact of YY1 overexpression and YY1 loss on lymphomagenesis and agressiveness.
5. Role of transcription factor PU.1 in hematopoietic development and enhancer chromatin structure. We found that PU.1 binds to immunoglobulin enhancers and recruits other proteins to DNA. Using PU.1 conditional knock-out mice and a variety of PU.1 mutants that ablate specific functions, we are exploring the role of PU.1 in enhancer chromatin structure, protein recruitment to DNA, and B cell development.