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VDJ Recombination

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https://www.readbyqxmd.com/read/28348365/e%C3%AE-and-3-rr-igh-enhancers-show-hierarchic-unilateral-dependence-in-mature-b-cells
#1
A Saintamand, C Vincent-Fabert, M Marquet, N Ghazzaui, V Magnone, E Pinaud, M Cogné, Y Denizot
Enhancer and super-enhancers are master regulators of cell fate. While they act at long-distances on adjacent genes, it is unclear whether they also act on one another. The immunoglobulin heavy chain (IgH) locus is unique in carrying two super-enhancers at both ends of the constant gene cluster: the 5'Eμ super-enhancer promotes VDJ recombination during the earliest steps of B-cell ontogeny while the 3' regulatory region (3'RR) is essential for late differentiation. Since they carry functional synergies in mature B-cells and physically interact during IgH locus DNA looping, we investigated if they were independent engines of locus remodelling or if their function was more intimately intermingled, their optimal activation then requiring physical contact with each other...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28294689/genomics-signaling-and-treatment-of-waldenstr%C3%A3-m-macroglobulinemia
#2
Zachary R Hunter, Guang Yang, Lian Xu, Xia Liu, Jorge J Castillo, Steven P Treon
Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88...
February 13, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28256716/assessing-microenvironment-immunogenicity-using-tumor-specimen-exomes-co-detection-of-tcr-%C3%AE-%C3%AE-v-d-j-recombinations-correlates-with-pd-1-expression
#3
Yaping N Tu, Wei Lue Tong, Mohammad D Samy, John M Yavorski, Minjung Kim, George Blanck
T-cell receptor (TcR) recombinations can be recovered from tumor specimen, whole exome sequences (WXS) files. However, it is not yet clear how these recombinations represent lymphocytes or an anti-tumor immune response. Here we report the identification of productive TcR-β recombinations in WXS files representing primary and metastatic melanoma. The recombinations are identifiable in about 20% of the cancer genome atlas melanoma samples. This frequency of detection is lower than the frequency of TcR-α VJ recombinations, consistent with the occurrence of biallelic TcR-α recombinations and possibly consistent with the fact that only one junctional recombination is required for TcR-α whereas two recombinations are required to form a TcR-β gene...
March 3, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28196891/insights-into-immune-system-development-and-function-from-mouse-t-cell-repertoires
#4
Zachary Sethna, Yuval Elhanati, Chrissy S Dudgeon, Curtis G Callan, Arnold J Levine, Thierry Mora, Aleksandra M Walczak
The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors. This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts on the surface receptor gene each time a new immune cell is created from a stem cell. By analyzing T-cell receptor (TCR) sequence repertoires taken from the blood and thymus of mice of different ages, we quantify the changes in the VDJ recombination process that occur from embryo to young adult...
February 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28169523/the-suv39h1-protein-lysine-methyltransferase-methylates-chromatin-proteins-involved-in-heterochromatin-formation-and-vdj-recombination
#5
Srikanth Kudithipudi, Maren Kirstin Schuhmacher, Adam Fiseha Kebede, Albert Jeltsch
SUV39H1 is an H3K9 methyltransferase involved in the formation of heterochromatin. We investigated its substrate specificity profile and show recognition of H3 residues between K4 and G12 with highly specific readout of R8. The specificity profile of SUV39H1 is distinct from its paralog SUV39H2, indicating that they can have different additional substrates. Using the specificity profile, several novel SUV39H1 candidate substrates were identified. We observed methylation of 19 novel substrates at the peptide level and for six of them at the protein level...
February 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28137913/chromatin-domain-organization-of-tcrb-locus-and-its-perturbation-by-ectopic-ctcf-binding
#6
Pratishtha Rawat, Manisha Jalan, Ananya Sadhu, Abhilasha Kanaujia, Madhulika Srivastava
CTCF mediated chromatin interactions influence organization and function of mammalian genome in diverse ways. We analyzed the interactions amongst CTCF binding sites (CBS) at murine TCRb locus to discern the role of CTCF mediated interactions in regulation of transcription and VDJ recombination. 3C analysis revealed thymocyte specific long-range intrachromosomal interactions amongst various CBS across the locus that were relevant for defining the limit of enhancer Eb regulated Recombination Centre (RC) and for facilitating the spatial proximity of Trbv segments to RC...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27995306/t-cell-receptor-gene-recombinations-in-human-tumor-specimen-exome-files-detection-of-t-cell-receptor-%C3%AE-vdj-recombinations-associates-with-a-favorable-oncologic-outcome-for-bladder-cancer
#7
Mohammad D Samy, Wei Lue Tong, John M Yavorski, Wade J Sexton, George Blanck
Understanding tumor-resident T cells is important for cancer prognosis and treatment options. Conventional, solid tumor specimen exome files can be searched directly for recombined T cell receptor (TcR)-α segments; RNASeq files can include TcR-β VDJ recombinations. To learn whether there are medically relevant uses of exome-based detection of TcR V(D)J recombinations in the tumor microenvironment, we searched cancer genome atlas and Moffitt Cancer Center, tumor specimen exome files for TcR-β, TcR-γ, and TcR-δ recombinations, for bladder and stomach cancer...
March 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27871274/chemotherapy-curable-malignancies-and-cancer-stem-cells-a-biological-review-and-hypothesis
#8
Philip Savage
BACKGROUND: Cytotoxic chemotherapy brings routine cures to only a small select group of metastatic malignancies comprising gestational trophoblast tumours, germ cell tumours, acute leukemia, Hodgkin's disease, high grade lymphomas and some of the rare childhood malignancies. We have previously postulated that the extreme sensitivity to chemotherapy for these malignancies is linked to the on-going high levels of apoptotic sensitivity that is naturally linked with the unique genetic events of nuclear fusion, meiosis, VDJ recombination, somatic hypermutation, and gastrulation that have occurred within the cells of origin of these malignancies...
November 21, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27686811/proteogenomics-for-the-comprehensive-analysis-of-human-cellular-and-serum-antibody-repertoires
#9
Paula Díez, Manuel Fuentes
The vast repertoire of immunoglobulins produced by the immune system is a consequence of the huge amount of antigens to which we are exposed every day. The diversity of these immunoglobulins is due to different mechanisms (including VDJ recombination, somatic hypermutation, and antigen selection). Understanding how the immune system is capable of generating this diversity and which are the molecular bases of the composition of immunoglobulins are key challenges in the immunological field. During the last decades, several techniques have emerged as promising strategies to achieve these goals, but it is their combination which appears to be the fruitful solution for increasing the knowledge about human cellular and serum antibody repertoires...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27472868/high-resolution-analysis-of-the-b-cell-repertoire-before-and-after-polyethylene-glycol-fusion-reveals-preferential-fusion-of-rare-antigen-specific-b-cells
#10
Axel R S X Dubois, Jean-Philippe Buerckert, Regina Sinner, William J Faison, Anne M Molitor, Claude P Muller
OBJECTIVE: The hybridoma technology is one of the most important advances in clinical immunology. Little is known about the differences between the antibodies produced during the in vivo immune response and those recovered in hybridoma libraries. Here, we investigate a potential fusion bias inherent to the hybridoma production process. METHODS: Transgenic rats carrying human Ig heavy and light chain loci were immunized with measles virus (MV) to generate human mAbs...
June 8, 2016: Human Antibodies
https://www.readbyqxmd.com/read/27301862/transcriptome-sequencing-reveals-a-profile-that-corresponds-to-genomic-variants-in-waldenstr%C3%A3-m-macroglobulinemia
#11
Zachary R Hunter, Lian Xu, Guang Yang, Nicholas Tsakmaklis, Josephine M Vos, Xia Liu, Jie Chen, Robert J Manning, Jiaji G Chen, Philip Brodsky, Christopher J Patterson, Joshua Gustine, Toni Dubeau, Jorge J Castillo, Kenneth C Anderson, Nikhil M Munshi, Steven P Treon
Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients...
August 11, 2016: Blood
https://www.readbyqxmd.com/read/27264181/two-mutually-exclusive-local-chromatin-states-drive-efficient-v-d-j-recombination
#12
Daniel J Bolland, Hashem Koohy, Andrew L Wood, Louise S Matheson, Felix Krueger, Michael J T Stubbington, Amanda Baizan-Edge, Peter Chovanec, Bryony A Stubbs, Kristina Tabbada, Simon R Andrews, Mikhail Spivakov, Anne E Corcoran
Variable (V), diversity (D), and joining (J) (V(D)J) recombination is the first determinant of antigen receptor diversity. Understanding how recombination is regulated requires a comprehensive, unbiased readout of V gene usage. We have developed VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products. We reveal a 200-fold range of recombination efficiency among recombining V genes in the primary mouse Igh repertoire. We used machine learning to integrate these data with local chromatin profiles to identify combinatorial patterns of epigenetic features that associate with active VH gene recombination...
June 14, 2016: Cell Reports
https://www.readbyqxmd.com/read/27149636/immunoglobulin-classification-using-the-colored-antibody-graph
#13
Stefano R Bonissone, Pavel A Pevzner
The somatic recombination of V, D, and J gene segments in B-cells introduces a great deal of diversity, and divergence from reference segments. Many recent studies of antibodies focus on the population of antibody transcripts that show which V, D, and J gene segments have been favored for a particular antigen, a repertoire. To properly describe the antibody repertoire, each antibody must be labeled by its constituting V, D, and J gene segment, a task made difficult by somatic recombination and hypermutation events...
June 2016: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
https://www.readbyqxmd.com/read/27102804/using-expected-sequence-features-to-improve-basecalling-accuracy-of-amplicon-pyrosequencing-data
#14
Thomas S Rask, Bent Petersen, Donald S Chen, Karen P Day, Anders Gorm Pedersen
BACKGROUND: Amplicon pyrosequencing targets a known genetic region and thus inherently produces reads highly anticipated to have certain features, such as conserved nucleotide sequence, and in the case of protein coding DNA, an open reading frame. Pyrosequencing errors, consisting mainly of nucleotide insertions and deletions, are on the other hand likely to disrupt open reading frames. Such an inverse relationship between errors and expectation based on prior knowledge can be used advantageously to guide the process known as basecalling, i...
April 22, 2016: BMC Bioinformatics
https://www.readbyqxmd.com/read/27102483/rna-binding-proteins-zfp36l1-and-zfp36l2-promote-cell-quiescence
#15
Alison Galloway, Alexander Saveliev, Sebastian Łukasiak, Daniel J Hodson, Daniel Bolland, Kathryn Balmanno, Helena Ahlfors, Elisa Monzón-Casanova, Sara Ciullini Mannurita, Lewis S Bell, Simon Andrews, Manuel D Díaz-Muñoz, Simon J Cook, Anne Corcoran, Martin Turner
Progression through the stages of lymphocyte development requires coordination of the cell cycle. Such coordination ensures genomic integrity while cells somatically rearrange their antigen receptor genes [in a process called variable-diversity-joining (VDJ) recombination] and, upon successful rearrangement, expands the pools of progenitor lymphocytes. Here we show that in developing B lymphocytes, the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 are critical for maintaining quiescence before precursor B cell receptor (pre-BCR) expression and for reestablishing quiescence after pre-BCR-induced expansion...
April 22, 2016: Science
https://www.readbyqxmd.com/read/27053761/internal-duplications-of-dh-jh-and-c-region-genes-create-an-unusual-igh-gene-locus-in-cattle
#16
Li Ma, Tong Qin, Dan Chu, Xueqian Cheng, Jing Wang, Xifeng Wang, Peng Wang, Haitang Han, Liming Ren, Robert Aitken, Lennart Hammarström, Ning Li, Yaofeng Zhao
It has been suspected for many years that cattle possess two functional IgH gene loci, located on Bos taurus autosome (BTA) 21 and BTA11, respectively. In this study, based on fluorescence in situ hybridization and additional experiments, we showed that all functional bovine IgH genes were located on BTA21, and only a truncated μCH2 exon was present on BTA11. By sequencing of seven bacterial artificial chromosome clones screened from a Hostein cow bacterial artificial chromosome library, we generated a 678-kb continuous genomic sequence covering the bovine IGHV, IGHD, IGHJ, and IGHC genes, which are organized as IGHVn-IGHDn-IGHJn-IGHM1-(IGHDP-IGHV3-IGHDn)3-IGHJn-IGHM2-IGHD-IGHG3-IGHG1-IGHG2-IGHE-IGHA...
May 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27047738/double-strand-break-repair-based-on-short-homology-regions-is-suppressed-under-terminal-deoxynucleotidyltransferase-expression-as-revealed-by-a-novel-vector-system-for-analysing-dna-repair-by-nonhomologous-end-joining
#17
So Maezawa, Saori Nakano, Takaaki Kuniya, Osamu Koiwai, Kotaro Koiwai
We have constructed a novel, nonhomologous end-joining (NHEJ) assay vector (NAV), containing mKate2, Venus and ccdB genes. Cotransfection of NAV with a construct expressing the restriction enzyme I-SceI generated a double-strand break (DSB) in NAV that excised mKate2 and ccdB. Repair of this DSB produced an intact vector that expressed Venus, a green fluorescent protein. Because cells bearing the repaired NAV lacked the ccdB gene which slows cell proliferation, the cultures were enriched in cells containing repaired DSBs...
January 2016: FEBS Open Bio
https://www.readbyqxmd.com/read/26941803/t-cell-receptor-phenotype-pattern-in-atopic-children-using-commercial-fluorescently-labeled-antibodies-against-21-human-class-specific-v-segments-for-the-tcr%C3%AE-chain-v%C3%AE-of-peripheral-blood-a-cross-sectional-study
#18
Gassem Gohal, Christine McCusker, Bruce Mazer, Reza Alizadehfar, Duncan Lejtenyi, Moshe Ben-Shoshan
BACKGROUND: T-cell receptor (TCR) repertoire development is an integral part of the adaptive immune response. T-cell activation requires recognition of appropriately processed antigens by the TCR. Development of a diverse repertoire of TCRs is therefore essential to ensure adequate protection from potential threats. The majority of T-cells in peripheral blood have TCRs composed of an alpha and a beta chain. At the DNA level, the TCR genes are formed through directed recombination from germline sequences-the so-called VDJ recombination [variable (V) joining (J) diversity (D) gene segments] which results in variations in the repertoire...
2016: Allergy, Asthma, and Clinical Immunology
https://www.readbyqxmd.com/read/26921311/restoration-of-atm-expression-in-dna-pkcs-deficient-cells-inhibits-signal-end-joining
#19
Jessica A Neal, Yao Xu, Masumi Abe, Eric Hendrickson, Katheryn Meek
Unlike most DNA-dependent protein kinase, catalytic subunit (DNA-PKcs)-deficient mouse cell strains, we show in the present study that targeted deletion of DNA-PKcs in two different human cell lines abrogates VDJ signal end joining in episomal assays. Although the mechanism is not well defined, DNA-PKcs deficiency results in spontaneous reduction of ATM expression in many cultured cell lines (including those examined in this study) and in DNA-PKcs-deficient mice. We considered that varying loss of ATM expression might explain differences in signal end joining in different cell strains and animal models, and we investigated the impact of ATM and/or DNA-PKcs loss on VDJ recombination in cultured human and rodent cell strains...
April 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/26873538/distinct-patterns-of-colocalization-of-the-ccnd1-and-cmyc-genes-with-their-potential-translocation-partner-igh-at-successive-stages-of-b-cell-differentiation
#20
Ilya Sklyar, Olga V Iarovaia, Alexey A Gavrilov, Andrey Pichugin, Diego Germini, Tatiana Tsfasman, Gersende Caron, Thierry Fest, Marc Lipinski, Sergey V Razin, Yegor S Vassetzky
The immunoglobulin heavy chain (IGH) locus is submitted to intra-chromosomal DNA breakages and rearrangements during normal B cell differentiation that create a risk for illegitimate inter-chromosomal translocations leading to a variety of B-cell malignancies. In most Burkitt's and Mantle Cell lymphomas, specific chromosomal translocations juxtapose the IGH locus with a CMYC or Cyclin D1 (CCND1) gene, respectively. 3D-fluorescence in situ hybridization was performed on normal peripheral B lymphocytes induced to mature in vitro from a naive state to the stage where they undergo somatic hypermutation (SHM) and class switch recombination (CSR)...
July 2016: Journal of Cellular Biochemistry
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