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.
Syrett Camille M, Paneru Bam, Sandoval-Heglund Donavon, Wang Jianle, Banerjee Sarmistha, Sindhava Vishal, Behrens Edward M, Atchison Michael, Anguera Montserrat C Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases. [PMID 30944248] JCI insight 4: , 2019.Zaprazna Kristina, Reblova Kamila, Svobodova Veronika, Radova Lenka, Bystry Vojtech, Baloun Jiri, Durechova Kristina, Tom Nikola, Loja Tomas, Buresova Martina, Stranska Kamila, Oltova Alexandra, Doubek Michael, Atchison Michael L, Trbusek Martin, Malcikova Jitka, Pospisilova Sarka Activation-induced deaminase and its splice variants associate with trisomy 12 in chronic lymphocytic leukemia. [PMID 30368590] Annals of hematology 98: 423-435, 2019.Syrett Camille M, Sindhava Vishal, Sierra Isabel, Dubin Aimee H, Atchison Michael, Anguera Montserrat C Diversity of Epigenetic Features of the Inactive X-Chromosome in NK Cells, Dendritic Cells, and Macrophages. [PMID 30671059] Frontiers in immunology 9: 3087, 2018.Zaprazna Kristina, Basu Arindam, Tom Nikola, Jha Vibha, Hodawadekar Suchita, Radova Lenka, Malcikova Jitka, Tichy Boris, Pospisilova Sarka, Atchison Michael L Transcription factor YY1 can control AID-mediated mutagenesis in mice. [PMID 29080214] European journal of immunology 48: 273-282, 2018.Syrett Camille M, Sindhava Vishal, Hodawadekar Suchita, Myles Arpita, Liang Guanxiang, Zhang Yue, Nandi Satabdi, Cancro Michael, Atchison Michael, Anguera Montserrat C Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells. [PMID 28991910] PLoS genetics 13: e1007050, 2017.Banerjee Anupam, Sindhava Vishal, Vuyyuru Raja, Jha Vibha, Hodewadekar Suchita, Manser Tim, Atchison Michael L YY1 Is Required for Germinal Center B Cell Development. [PMID 27167731] PloS one 11: e0155311, 2016.Wang Jianle, Syrett Camille M, Kramer Marianne C, Basu Arindam, Atchison Michael L, Anguera Montserrat C Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. [PMID 27001848 ] Proceedings of the National Academy of Sciences of the United States of America 113: E2029-38, 2016.Mehra Parul, Gerasimova Tatiana, Basu Arindam, Jha Vibha, Banerjee Anupam, Sindhava Vishal, Gray Falon, Berry Corbett T, Sen Ranjan, Atchison Michael L YY1 controls Eµ-3'RR DNA loop formation and immunoglobulin heavy chain class switch recombination. [PMID 29167838] Blood advances 1: 15-20, 2016.Atchison Michael L Function of YY1 in Long-Distance DNA Interactions. [PMID 24575094] Frontiers in immunology 5: 45, 2014.Basu Arindam, Wilkinson Frank H, Colavita Kristen, Fennelly Colin, Atchison Michael L YY1 DNA binding and interaction with YAF2 is essential for Polycomb recruitment. [PMID 24285299] Nucleic acids research 42: 2208-23, 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. [PMID 23531880 ] The EMBO journal 32: 1168-82, 2013.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. [PMID 22292011] PloS one 7: e30656, 2012.Zaprazna Kristina, Atchison Michael L YY1 controls immunoglobulin class switch recombination and nuclear activation-induced deaminase levels. [PMID 22290437] 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. [PMID 22279106] Journal of immunology (Baltimore, Md. : 1950) 188: 2276-84, 2012.Atchison Michael, Basu Arindam, Zaprazna Kristina, Papasani Madhusudhan Mechanisms of Yin Yang 1 in oncogenesis: the importance of indirect effects. [PMID 22248052] 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.[PMID 20082324] 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.[PMID 19960508] 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. [PMID 19564417] Molecular and cellular biology 29: 4612-22, 2009.Atchison Michael L Factors that attract veterinarians to or discourage them from research careers: a program director's perspective.[PMID 19435993] Journal of veterinary medical education 36: 76-82, 2009.Buss Daryl D, Atchison Michael L, Corps Kara N, Falkowski Lauren B, Fox James G, Hendricks Joan C, Mexas Angela M, Rosol Thomas J, Stromberg Bert E Veterinarians in biomedical research: building national capacity. [PMID 19435991] Journal of veterinary medical education 36: 62-9, 2009.