Control of B and T cell Development and Epigenetic Mechanisms.
Key words: Transcription, Epigenetics, Lineage Development, Long distance DNA interactions.
The Atchison laboratory studies the molecular mechanisms responsible for transcriptional regulation, epigenetic processes, and the control of B and T cell lineage development.
Much of our work currently focuses on the function of transcription factor YY1 in controlling hematopoietic lineage commitment via long-range chromatin interactions coupled with repressive histone modifications. Interestingly, conditional knockout of YY1 in the B cell lineage enables YY1-null pro-B cells to develop into the T cell lineage both in vitro and in vivo. In addition, we found YY1-null pro-B cells are able to dedifferentiate into hematopoietic precursor cells, and to differentiate into numerous alternative lineages. Our studies may define a universal mechanism for lineage commitment that may be manipulated both experimentally, as well as therapeutically.
Key questions being addressed include:
1. What is the mechanism of B lineage commitment? We hypothesize that YY1 is recruited early in lineage development to key locations in the genome by action of pioneer transcription factors. YY1 subsequently forms and stabilizes long distance DNA interactions at lineage-appropriate genes, and recruits the Polycomb Group complex to generate H2K27me3 modifications at alternative lineage genes. We hypothesize these two processes stabilize lineage commitment.
2. What is the mechanism of YY1 control of chromatin structures that regulate commitment? We are testing in vitro and in vivo key YY1 mutants that ablate specific YY1 functions such as transcriptional activation, Polycomb recruitment, self-association, and DNA binding, for their impact on chromatin structure, long-distance DNA interactions, and immunoglobulin locus contraction needed for V(D)J rearrangement.
3. What is the breadth of hematopoietic plasticity caused by YY1 knockout? Using lineage-specific CRE drivers and a Rosa26-Cherry readout, we are determining the numerous hematopoietic lineages that can develop from YY1-null pro-B cells. These studies are showing unusual levels of lineage plasticity caused by YY1 knock-out.
4. What are the molecular and functional fidelities of alternative lineage cells that develop from YY1-null pro-B cells? Using Hi-C, ChIP-seq, ATAC-seq, RNA-seq, and proteomic approaches we are determining the molecular fidelity of T lineage cells that develop from YY1-null pro-B cells. These molecular studies are being complemented with cellular assays to measure T cell functions.
5. Are T lineage cells equally developmentally plastic after YY1 knockout? As we hypothesize that the mechanism we have identified is commonly used in lineage commitment, we anticipate that other hematopoietic lineages will be developmentally plastic after YY1 knockout.
Michael Atchison, Ph.D. P.I.
Frank Wilkinson, Ph.D. Visiting Scientist
Arindam Basu, Ph.D. Visiting Scientist
Suchita Hodawadekar, M.S. Research Specialist
Sarmistha Banerjee, Ph.D. Research Associate
Qiu X, Ma F, Zhao M, Cao Y, Shipp L, Liu A, Dutta A, Singh A, Braikia FZ, De S, Wood WH 3rd, Becker KG, Zhou W, Ji H, Zhao K, Atchison ML, Sen R. Altered 3D chromatin structure permits inversional recombination at the IgH locus Sci Adv 6: eaaz8850, 2020.Nandi S, Liang G, Sindhava V, Angireddy R, Basu A, Banerjee S, Hodawadekar S, Zhang Y, Avadhani NG, Sen R, Atchison ML. YY1 control of mitochondrial-related genes does not account for regulation of immunoglobulin class switch recombination in mice Eur J Immunol 50: 822-838, 2020.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, 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: e126751, 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.