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 fiscal year are: 1- Rao et al., Cell, October 2017. In this manuscript we showed in collaboration with Erez Lieberman from Baylor that loss of cohesin leads to a complete elimination of loops and loop domains, which are key for gene transcription 2- Vian et al, Cell, May 2018. In this publication we elucidate how nuclear architecture is assembled in B and ES cells and its impact on transcription.

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Budget End
Support Year
14
Fiscal Year
2018
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Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
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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
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

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