Our main goal is to unravel the nuclear events that drive peripheral activation of B lymphocytes: from genome-wide changes in epigenetics, chromatin architecture, and transcriptional activation, to recombination and hypermutation of antibody genes. Another major interest is to understand how deregulation of these mechanisms leads to B cell tumorigenesis and autoimmunity. To achieve these goals, our team combines a wide range of cutting-edge technologies, including genome editing, nanoscopy, in situ Hi-C, cryo-EM, and bioinformatic tools. B lymphocytes in higher organisms are born in the bone marrow, where they expand and undergo antibody gene recombination to assemble their cell surface receptors. The newly generated B cells then migrate to the periphery as quiescent lymphocytes. In this metabolically inert state, B cells can live for up to 4 months. If during their lifespan they encounter foreign antigens, nave B cells become activated and enter the cell cycle in less than 24h. How B lymphocytes are able to respond so rapidly to infection has been a mystery. In the past year, we have partially resolved this puzzle by showing that the genome of nave B cells is poised. RNA polymerases, transcription factors, chromatin remodelers, histone acetyl and methyltransferases, and nuclear architectural proteins are all recruited to chromatin in a manner nearly identical to that seen in activated counterparts. In nave cells, the preloaded enzymes only display basal activity until an optimal concentration of their catalytic substrates or cofactors is reached during activation. Taking transcription as an example, a comparative analysis between quiescent and cycling cells shows that expression of all genes is proportionally amplified 10 fold. In addition, the architecture of proteins (histones) around which DNA is wrapped changes drastically during the immune response. Our most important manuscripts dealing with B cell activation and histone-DNA architectural changes this year are: 1- Canela et al, Cell, July 2017. In this manuscript we showed in collaboration with Andre Nussenzweig from NCI that topoisomerases induce DNA breaks to untangle B cell histone-DNA. Notably, these DNA lesions occur at sites known to be damaged in human tumors, raising the prospect that nuclear architecture can promote cell transformation. 2- Kieffer-Kwon et al, Molecular Cell, August 2017. In this publication we demonstrate that the genome of quiescent B cells is poised for activation to facilitate their participation in the immune response. 3- Another project we are currently working on is the generation of mice that can produce human antibodies. To this end, we are using CRISPR and other editing tools to modify the genome of mouse ES cells. We anticipate that this new tool will be instrumental in the development of therapies against viral diseases (HIV, dengue) as well as autoimmunity and cancer.

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Li, Guideng; So, Alex Yick-Lun; Sookram, Reeshelle et al. (2018) Epigenetic silencing of miR-125b is required for normal B-cell development. Blood 131:1920-1930
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
Rao, Suhas S P; Huang, Su-Chen; Glenn St Hilaire, Brian et al. (2017) Cohesin Loss Eliminates All Loop Domains. Cell 171:305-320.e24
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
Aiden, Erez Lieberman; Casellas, Rafael (2015) Somatic Rearrangement in B Cells: It's (Mostly) Nuclear Physics. Cell 162:708-11

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