B lymphocytes recognize and destroy viruses and bacteria through antibodies. These molecules are secreted during the immune response, when B cells encounter and recognize foreign material on the surface of pathogens. Unlike other genes, antibody genes are assembled by the joining of various DNA segments thorough a reaction known as V(D)J recombination. The enzymes responsible for V(D)J recombination are called RAG1 and RAG2. Recombination occurs very early on in development, when B cells are still maturing in the bone marrow. Once the antibody molecule is placed on the cell surface B cells migrate out of the bone marrow via blood vessels to the periphery, where they scan the environment for foreign materials. Whenever the antibody molecule on the B cell surface is crosslinked by bacterial or viral proteins, B cells become activated and engage in the immune response. One of the most striking aspects of this response is that the affinity of the antibody molecule for foreign proteins increases over time. This is achieved by the introduction of random mutations in the antibody genes by an enzyme called AID. While RAG and AID preferentially target antibody genes, other genomic sites, including the Myc and Pim1 oncogenes, undergo low levels of DNA damage. This off-targeting activity can produce rearrangements that have the potential to deregulate oncogenes, leading to B cell tumor development. Why RAGs and AID are thus promiscuous has been a mystery. Another important aspect of B cell activation we are interested in concerns the mechanisms driving resting cells to readily enter the cell cycle during the immune response. This fiscal year our laboratory published a few manuscripts dealing with the above questions and made great progress on several projects that explore B cell activation from a holistic view: 1- Zhang et al, Nucleic Acids Research, April 2016. In this manuscript we showed in collaboration with Michael Bustin from the NCI that HMGN proteins, a family of chromatin binding factors, modulate gene regulatory sites during B cell activation. The new data help explain how these domains become more accessible to the recruitment of transcription factors, proteins that enhance gene expression. 2- Casellas et al, Nature Review Immunology, March 2016. In this publication we review how genomic research in the past 7 years has uncovered the basic mechanisms behind AID promiscuous activity. 3- Swaminathan et al, Nature Immunology, July 2015. In collaboration with Markus Muschen from UCSF, we showed how AID and RAGs cooperate to render pre-leukemic B cells into full blown tumors during development of childhood acute lymphoblastic leukemia (ALL). 4- Pratama et al, Nature Communications, March 2015. In this manuscript, we collaborated with Carola Vinuesa from the John Curtin School of Medical Research to uncover a microRNA (146a) that regulates the accumulation of helper T cells during the B cell response in germinal centers.

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Arthritis, Musculoskeletal, Skin Dis
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Juan, Aster H; Wang, Stan; Ko, Kyung Dae et al. (2017) Roles of H3K27me2 and H3K27me3 Examined during Fate Specification of Embryonic Stem Cells. Cell Rep 18:297
Kouzine, Fedor; Wojtowicz, Damian; Baranello, Laura et al. (2017) Permanganate/S1 Nuclease Footprinting Reveals Non-B DNA Structures with Regulatory Potential across a Mammalian Genome. Cell Syst 4:344-356.e7
Kieffer-Kwon, Kyong-Rim; Nimura, Keisuke; Rao, Suhas S P et al. (2017) Myc Regulates Chromatin Decompaction and Nuclear Architecture during B Cell Activation. Mol Cell 67:566-578.e10
Wang, Qiao; Kieffer-Kwon, Kyong-Rim; Oliveira, Thiago Y et al. (2017) The cell cycle restricts activation-induced cytidine deaminase activity to early G1. J Exp Med 214:49-58
Canela, Andres; Maman, Yaakov; Jung, Seolkyoung et al. (2017) Genome Organization Drives Chromosome Fragility. Cell 170:507-521.e18
Zhang, Shaofei; Zhu, Iris; Deng, Tao et al. (2016) HMGN proteins modulate chromatin regulatory sites and gene expression during activation of naïve B cells. Nucleic Acids Res :
Casellas, Rafael; Basu, Uttiya; Yewdell, William T et al. (2016) Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nat Rev Immunol 16:164-76
Pratama, Alvin; Srivastava, Monika; Williams, Naomi J et al. (2015) MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat Commun 6:6436
Swaminathan, Srividya; Klemm, Lars; Park, Eugene et al. (2015) Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat Immunol 16:766-774
Teng, Grace; Maman, Yaakov; Resch, Wolfgang et al. (2015) RAG Represents a Widespread Threat to the Lymphocyte Genome. Cell 162:751-65

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