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Daniel J Hodson, Arthur L Shaffer, Wenming Xiao, George W Wright, Roland Schmitz, James D Phelan, Yandan Yang, Daniel E Webster, Lixin Rui, Holger Kohlhammer, Masao Nakagawa, Thomas A Waldmann, Louis M Staudt
The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B...
April 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Zichong Li, Huasong Lu, Qiang Zhou
Promoter-proximal pausing by RNA polymerase II (Pol II) is a key rate-limiting step in HIV-1 transcription and latency reversal. The viral Tat protein recruits human super elongation complexes (SECs) to paused Pol II to overcome this restriction. Despite the recent progress in understanding the functions of different subsets of SECs in controlling cellular and Tat-activated HIV transcription, little is known about the SEC subtypes that help reverse viral latency in CD4(+) T cells. Here, we used the CRISPR-Cas9 genome-editing tool to knock out the gene encoding the SEC subunit ELL2, AFF1, or AFF4 in Jurkat/2D10 cells, a well-characterized HIV-1 latency model...
April 2016: Molecular and Cellular Biology
Martina Minnich, Hiromi Tagoh, Peter Bönelt, Elin Axelsson, Maria Fischer, Beatriz Cebolla, Alexander Tarakhovsky, Stephen L Nutt, Markus Jaritz, Meinrad Busslinger
The transcription factor Blimp-1 is necessary for the generation of plasma cells. Here we studied its functions in plasmablast differentiation by identifying regulated Blimp-1 target genes. Blimp-1 promoted the migration and adhesion of plasmablasts. It directly repressed genes encoding several transcription factors and Aicda (which encodes the cytidine deaminase AID) and thus silenced B cell-specific gene expression, antigen presentation and class-switch recombination in plasmablasts. It directly activated genes, which led to increased expression of the plasma cell regulator IRF4 and proteins involved in immunoglobulin secretion...
March 2016: Nature Immunology
Bhairavi Swaminathan, Guðmar Thorleifsson, Magnus Jöud, Mina Ali, Ellinor Johnsson, Ram Ajore, Patrick Sulem, Britt-Marie Halvarsson, Guðmundur Eyjolfsson, Vilhelmina Haraldsdottir, Christina Hultman, Erik Ingelsson, Sigurður Y Kristinsson, Anna K Kähler, Stig Lenhoff, Gisli Masson, Ulf-Henrik Mellqvist, Robert Månsson, Sven Nelander, Isleifur Olafsson, Olof Sigurðardottir, Hlif Steingrimsdóttir, Annette Vangsted, Ulla Vogel, Anders Waage, Hareth Nahi, Daniel F Gudbjartsson, Thorunn Rafnar, Ingemar Turesson, Urban Gullberg, Kári Stefánsson, Markus Hansson, Unnur Thorsteinsdóttir, Björn Nilsson
Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells...
2015: Nature Communications
Li Xu, Hongwei Tang, Diane W Chen, Adel K El-Naggar, Peng Wei, Erich M Sturgis
BACKGROUND: Salivary gland carcinomas (SGCs) are a rare malignancy with unknown etiology. The objective of the current study was to identify genetic variants modifying the risk of SGC and its major subtypes: adenoid cystic carcinoma and mucoepidermoid carcinoma. METHODS: The authors conducted a genome-wide association study in 309 well-defined SGC cases and 535 cancer-free controls. A single-nucleotide polymorphism (SNP)-level discovery study was performed in non-Hispanic white individuals followed by a replication study in Hispanic individuals...
July 15, 2015: Cancer
Ian Bayles, Christine Milcarek
B cells can be activated by cognate antigen, anti-B-cell receptor antibody, complement receptors, or polyclonal stimulators like lipopolysaccharide; the overall result is a large shift in RNA processing to the secretory-specific form of immunoglobulin (Ig) heavy chain mRNA and an upregulation of Igh mRNA amounts. Associated with this shift is the large-scale induction of Ig protein synthesis and the unfolded protein response to accommodate the massive quantity of secretory Ig that results. Stimulation to secretion also produces major structural accommodations and stress, with extensive generation of endoplasmic reticulum and Golgi as part of the cellular architecture...
2014: Critical Reviews in Immunology
Yasuhito Funahashi, Zhou Wang, Katherine J O'Malley, Pradeep Tyagi, Donald B DeFranco, Jeffrey R Gingrich, Ryosuke Takahashi, Tsuyoshi Majima, Momokazu Gotoh, Naoki Yoshimura
BACKGROUND: Prostatic inflammation is reportedly associated with the development of prostatic hyperplasia. We investigated the effects of prostatic inflammation on expression levels of androgen-responsive genes and growth factors in the rat prostate. METHODS: Prostatic inflammation was induced by Escherichia coli (strain 1677) injection (0.2 ml of 1 × 10(8) CFU/ml) into the prostatic urethra of male Sprague-Dawley rats, and ventral lobes of the prostate were harvested on day 84...
March 1, 2015: Prostate
Kyung Soo Park, Ian Bayles, Alec Szlachta-McGinn, Joshua Paul, Julie Boiko, Patricia Santos, June Liu, Zhou Wang, Lisa Borghesi, Christine Milcarek
Differentiation of B cells into Ab-secreting cells induces changes in gene transcription, IgH RNA processing, the unfolded protein response (UPR), and cell architecture. The transcription elongation factor eleven nineteen lysine-rich leukemia gene (ELL2) stimulates the processing of the secreted form of the IgH mRNA from the H chain gene. Mice (mus musculus) with the ELL2 gene floxed in either exon 1 or exon 3 were constructed and crossed to CD19-driven cre/CD19(+). The B cell-specific ELL2 conditional knockouts (cKOs; ell2(loxp/loxp) CD19(cre/+)) exhibit curtailed humoral responses both in 4-hydroxy-3-nitrophenyl acetyl-Ficoll and in 4-hydroxy-3-nitrophenyl acetyl-keyhole limpet hemocyanin immunized animals; recall responses were also diminished...
November 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Melanie C Mann, Sarah Strobel, Bernhard Fleckenstein, Andrea K Kress
The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression...
September 2014: Virology
Pingyang Liu, Yanhui Xiang, Koh Fujinaga, Koen Bartholomeeusen, Kyle A Nilson, David H Price, B Matija Peterlin
By phosphorylating negative elongation factors and the C-terminal domain of RNA polymerase II (RNAPII), positive transcription elongation factor b (P-TEFb), which is composed of CycT1 or CycT2 and CDK9, activates eukaryotic transcription elongation. In growing cells, it is found in active and inactive forms. In the former, free P-TEFb is a potent transcriptional coactivator. In the latter, it is inhibited by HEXIM1 or HEXIM2 in the 7SK small nuclear ribonucleoprotein (snRNP), which contains, additionally, 7SK snRNA, methyl phosphate-capping enzyme (MePCE), and La-related protein 7 (LARP7)...
April 4, 2014: Journal of Biological Chemistry
Seemay Chou, Heather Upton, Katherine Bao, Ursula Schulze-Gahmen, Avi J Samelson, Nanhai He, Anna Nowak, Huasong Lu, Nevan J Krogan, Qiang Zhou, Tom Alber
The HIV-1 Tat protein stimulates viral gene expression by recruiting human transcription elongation complexes containing P-TEFb, AFF4, ELL2, and ENL or AF9 to the viral promoter, but the molecular organization of these complexes remains unknown. To establish the overall architecture of the HIV-1 Tat elongation complex, we mapped the binding sites that mediate complex assembly in vitro and in vivo. The AFF4 protein emerges as the central scaffold that recruits other factors through direct interactions with short hydrophobic regions along its structurally disordered axis...
January 8, 2013: Proceedings of the National Academy of Sciences of the United States of America
Nora Franceschini, Frank J A van Rooij, Bram P Prins, Mary F Feitosa, Mahir Karakas, John H Eckfeldt, Aaron R Folsom, Jeffrey Kopp, Ahmad Vaez, Jeanette S Andrews, Jens Baumert, Vesna Boraska, Linda Broer, Caroline Hayward, Julius S Ngwa, Yukinori Okada, Ozren Polasek, Harm-Jan Westra, Ying A Wang, Fabiola Del Greco M, Nicole L Glazer, Karen Kapur, Ido P Kema, Lorna M Lopez, Arne Schillert, Albert V Smith, Cheryl A Winkler, Lina Zgaga, Stefania Bandinelli, Sven Bergmann, Mladen Boban, Murielle Bochud, Y D Chen, Gail Davies, Abbas Dehghan, Jingzhong Ding, Angela Doering, J Peter Durda, Luigi Ferrucci, Oscar H Franco, Lude Franke, Grog Gunjaca, Albert Hofman, Fang-Chi Hsu, Ivana Kolcic, Aldi Kraja, Michiaki Kubo, Karl J Lackner, Lenore Launer, Laura R Loehr, Guo Li, Christa Meisinger, Yusuke Nakamura, Christine Schwienbacher, John M Starr, Atsushi Takahashi, Vesela Torlak, André G Uitterlinden, Veronique Vitart, Melanie Waldenberger, Philipp S Wild, Mirna Kirin, Tanja Zeller, Tatijana Zemunik, Qunyuan Zhang, Andreas Ziegler, Stefan Blankenberg, Eric Boerwinkle, Ingrid B Borecki, Harry Campbell, Ian J Deary, Timothy M Frayling, Christian Gieger, Tamara B Harris, Andrew A Hicks, Wolfgang Koenig, Christopher J O' Donnell, Caroline S Fox, Peter P Pramstaller, Bruce M Psaty, Alex P Reiner, Jerome I Rotter, Igor Rudan, Harold Snieder, Toshihiro Tanaka, Cornelia M van Duijn, Peter Vollenweider, Gerard Waeber, James F Wilson, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Alan F Wright, Qingyu Wu, Yongmei Liu, Nancy S Jenny, Kari E North, Janine F Felix, Behrooz Z Alizadeh, L Adrienne Cupples, John R B Perry, Andrew P Morris
Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21...
October 5, 2012: American Journal of Human Genetics
Micah J Benson, Tarmo Aijö, Xing Chang, John Gagnon, Utz J Pape, Vivek Anantharaman, L Aravind, Juha-Pekka Pursiheimo, Shalini Oberdoerffer, X Shirley Liu, Riitta Lahesmaa, Harri Lähdesmäki, Anjana Rao
B cells and plasma cells possess distinct RNA processing environments that respectively promote the expression of membrane-associated Ig by B cells versus the secretion of Ig by plasma cells. Through a combination of transcriptional profiling and screening using a lentiviral short-hairpin RNA interference library, we show that both the splicing factor hnRNPLL and the transcription elongation factor ELL2 modulate the ratio of secreted versus membrane-encoding Ighg2b transcripts in MPC11 plasmacytoma cell lines...
October 2, 2012: Proceedings of the National Academy of Sciences of the United States of America
Koen Bartholomeeusen, Yanhui Xiang, Koh Fujinaga, B Matija Peterlin
By phosphorylating elongation factors and the C-terminal domain of RNA polymerase II, the positive transcription elongation factor b (P-TEFb) is the critical kinase for transcription elongation and co-transcriptional processing of eukaryotic genes. It exists in inactive small nuclear ribonucleoprotein (7SK snRNP) and active (free P-TEFb) complexes in cells. The P-TEFb equilibrium determines the state of cellular activation, proliferation, and differentiation. Free P-TEFb, which is required for growth, can be recruited to RNA polymerase II via transcription factors, BRD4, or the super elongation complex (SEC)...
October 19, 2012: Journal of Biological Chemistry
Hui Zhang, Xiaoxiang Hu, Zhipeng Wang, Yuandan Zhang, Shouzhi Wang, Ning Wang, Li Ma, Li Leng, Shengwen Wang, Qigui Wang, Yuxiang Wang, Zhiquan Tang, Ning Li, Yang Da, Hui Li
We conducted a selection signature analysis using the chicken 60k SNP chip in two chicken lines that had been divergently selected for abdominal fat content (AFC) for 11 generations. The selection signature analysis used multiple signals of selection, including long-range allele frequency differences between the lean and fat lines, long-range heterozygosity changes, linkage disequilibrium, haplotype frequencies, and extended haplotype homozygosity. Multiple signals of selection identified ten signatures on chromosomes 1, 2, 4, 5, 11, 15, 20, 26 and Z...
2012: PloS One
Min Liu, Joanne Hsu, Caleb Chan, Zichong Li, Qiang Zhou
Super elongation complexes (SECs) contain two different transcription elongation factors, P-TEFb and ELL1/2, linked by the scaffolding protein AFF4 or AFF1. They stimulate the expression of both normal and disease-related genes, especially those of HIV or those involved in leukemogenesis. Among all SEC subunits, ELL2 is stoichiometrically limiting and uniquely regulated at the level of protein stability. Here we identify the RING domain protein Siah1, but not the homologous Siah2, as the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation...
May 11, 2012: Molecular Cell
Nanhai He, Caleb K Chan, Bijan Sobhian, Seemay Chou, Yuhua Xue, Min Liu, Tom Alber, Monsef Benkirane, Qiang Zhou
The Super Elongation Complex (SEC), containing transcription elongation activators/coactivators P-TEFb, ELL2, AFF4/1, ENL, and AF9, is recruited by HIV-1 Tat and mixed lineage leukemia (MLL) proteins to activate the expression of HIV-1 and MLL-target genes, respectively. In the absence of Tat and MLL, however, it is unclear how SEC is targeted to RNA polymerase (Pol) II to stimulate elongation in general. Furthermore, although ENL and AF9 can bind the H3K79 methyltransferase Dot1L, it is unclear whether these bindings are required for SEC-mediated transcription...
September 6, 2011: Proceedings of the National Academy of Sciences of the United States of America
Christine Milcarek, Michael Albring, Creityeka Langer, Kyung Soo Park
In plasma cells, immunoglobulin heavy chain (IgH) secretory-specific mRNA is made in high abundance as a result of both increased promoter proximal poly(A) site choice and weak splice-site skipping. Ell2, the eleven-nineteen lysine rich leukemia gene, is a transcription elongation factor that is induced ∼6-fold in plasma cells and has been shown to drive secretory-specific mRNA production. Reducing ELL2 by siRNA, which reduced processing to the secretion-specific poly(A) site, also influenced the methylations of histone H3K4 and H3K79 on the IgH gene and impacted positive transcription factor b (pTEFb), Ser-2 carboxyl-terminal phosphorylation, and polyadenylation factor additions to RNA polymerase II...
September 30, 2011: Journal of Biological Chemistry
Patricia Santos, Fortuna Arumemi, Kyung Soo Park, Lisa Borghesi, Christine Milcarek
B cell development starts in the bone marrow where hematopoietic stem cells (HSCs) progress through sequential developmental stages, as it differentiates into a naïve B cell expressing surface immunoglobulin. In the periphery, B cells that encounter antigen can further differentiate into antibody-secreting plasma cells. In this review, we focus on two factors, E47 and ELL2, which play important roles in the regulation of B cell development in the bone marrow and differentiation of mature B cells into plasma cells in the periphery, respectively...
August 2011: Immunologic Research
Damian G Romero, Elise P Gomez-Sanchez, Celso E Gomez-Sanchez
Transcription regulatory genes are crucial modulators of cell physiology and metabolism whose intracellular levels are tightly controlled in response to extracellular stimuli. We previously reported a set of 29 transcription regulatory genes modulated by angiotensin II in H295R human adrenocortical cells and their roles in regulating the expression of the last and unique enzymes of the glucocorticoid and mineralocorticoid biosynthetic pathways, 11β-hydroxylase and aldosterone synthase, respectively, using gene expression reporter assays...
November 29, 2010: Physiological Genomics
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