Control of B Cell Development, Gene Expression, and Oncogenesis.
Key words: Transcription, Immunoglobulin, B Cell Development, Long distance DNA interactions, Polycomb Group, Oncogenesis.
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.
Michael Atchison, Ph.D. P.I.
Dr. Atchison tries to work in the lab, and on occasion, actually succeeds. Recent projects include the function of YY1 in developing organisms and the role of enhancer binding factors in .
Frank Wilkinson, Ph.D. Visiting Scientist
Dr. Wilkinson is studying interaction of YY1 with other PcG proteins. He is also using transgenic approaches to define specific YY1 regions needed for specific molecular functions.
Arindam Basu, Ph.D. Visiting Scientist
Dr. Basu is studying PcG transcriptional control mechanisms regulated by YY1.
Parul Mehra, Ph.D. Post-doc
Dr. Mehra is exploring the function of YY1 in controlling long-distance DNA interactions at the Ig loci.
Suchita Hodawadekar, B.S. Research Specialist
Ms. Hodawadekar is studying developmental alterations in chromatin structure at the mouse Ig locus using chromatin immunoprecipitation assays. She is is studying the role of PU.1 and STAT5 in controlling Ig kappa locus activity.
Aisha Ghias, Part time Research Specialist
Ms. Ghias is studying the protein complexes that bind to the Ig kappa enhancers.
Xuan Pan, VMD, PhD
Dr. Pan received her PhD in 2010 in the Atchison laboratory and is now an Assistant Professor at the University of Wisconsin.
Kristina Zaprazna, Ph.D
Dr. Zaprazna received her PhD in 2011 in the Atchison laboratory and is now a faculty member at the Brno Institute in the Czech Republic.
Basu Arindam, Wilkinson Frank H, Colavita Kristen, Fennelly Colin, Atchison Michael L YY1 DNA binding and interaction with YAF2 is essential for Polycomb recruitment. Nucleic acids research 42: 2208-23, 2014.Atchison Michael L Function of YY1 in Long-Distance DNA Interactions. Frontiers in immunology 5: 45, 2014.Pan Xuan, Papasani Madhusudhan, Hao Yi, Calamito Marco, Wei Fang, Quinn Iii William J, Basu Arindam, Wang Junwen, Hodawadekar Suchita, Zaprazna Kristina, Liu Huifei, Shi Yang, Allman David, Cancro Michael, Atchison Michael L YY1 controls Ig? repertoire and B-cell development, and localizes with condensin on the Ig? locus. The EMBO journal 32: 1168-82, 2013.Zaprazna Kristina, Atchison Michael L YY1 controls immunoglobulin class switch recombination and nuclear activation-induced deaminase levels. Molecular and cellular biology 32: 1542-54, 2012.Hodawadekar Suchita, Park Kyoungsook, Farrar Michael A, Atchison Michael L A developmentally controlled competitive STAT5-PU.1 DNA binding mechanism regulates activity of the Ig ? E3' enhancer. Journal of immunology (Baltimore, Md. : 1950) 188: 2276-84, 2012.Pan Xuan, Jones Morgan, Jiang Jie, Zaprazna Kristina, Yu Duonan, Pear Warren, Maillard Ivan, Atchison Michael L Increased expression of PcG protein YY1 negatively regulates B cell development while allowing accumulation of myeloid cells and LT-HSC cells. PloS one 7: e30656, 2012.Atchison Michael, Basu Arindam, Zaprazna Kristina, Papasani Madhusudhan Mechanisms of Yin Yang 1 in oncogenesis: the importance of indirect effects. Critical reviews in oncogenesis 16: 143-61, 2011.Basu Arindam, Atchison Michael L CtBP levels control intergenic transcripts, PHO/YY1 DNA binding, and PcG recruitment to DNA. Journal of cellular biochemistry 110: 62-9, 2010.Wilkinson Frank, Pratt Heather, Atchison Michael L PcG recruitment by the YY1 REPO domain can be mediated by Yaf2. Journal of cellular biochemistry 109: 478-86, 2010.Wei Fang, Zaprazna Kristina, Wang Junwen, Atchison Michael L PU.1 can recruit BCL6 to DNA to repress gene expression in germinal center B cells. Molecular and cellular biology 29: 4612-22, 2009.