A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells.

Abstract:

:The super-enhancers (SEs) of lineage-specific genes in B cells are off-target sites of somatic hypermutation. However, the inability to detect sufficient numbers of mutations in normal human B cells has precluded the generation of a high-resolution mutational landscape of SEs. Here we captured and sequenced 12 B cell SEs at single-nucleotide resolution from 10 healthy individuals across diverse ethnicities. We detected a total of approximately 9,000 subclonal mutations (allele frequencies <0.1%); of these, approximately 8,000 are present in the BCL6 SE alone. Within the BCL6 SE, we identified 3 regions of clustered mutations in which the mutation frequency is ∼7 × 10-4 Mutational spectra show a predominance of C > T/G > A and A > G/T > C substitutions, consistent with the activities of activation-induced-cytidine deaminase (AID) and the A-T mutator, DNA polymerase η, respectively, in mutagenesis in normal B cells. Analyses of mutational signatures further corroborate the participation of these factors in this process. Single base substitution signatures SBS85, SBS37, and SBS39 were found in the BCL6 SE. While SBS85 is a denoted signature of AID in lymphoid cells, the etiologies of SBS37 and SBS39 are unknown. Our analysis suggests the contribution of error-prone DNA polymerases to the latter signatures. The high-resolution mutation landscape has enabled accurate profiling of subclonal mutations in B cell SEs in normal individuals. By virtue of the fact that subclonal SE mutations are clonally expanded in B cell lymphomas, our studies also offer the potential for early detection of neoplastic alterations.

authors

Shen JC,Kamath-Loeb AS,Kohrn BF,Loeb KR,Preston BD,Loeb LA

doi

10.1073/pnas.1914163116

subject

Has Abstract

pub_date

2019-12-03 00:00:00

pages

24779-24785

issue

49

eissn

0027-8424

issn

1091-6490

pii

1914163116

journal_volume

116

pub_type

杂志文章
  • Mechanism of action of a pestivirus antiviral compound.

    abstract::We report here the discovery of a small molecule inhibitor of pestivirus replication. The compound, designated VP32947, inhibits the replication of bovine viral diarrhea virus (BVDV) in cell culture at a 50% inhibitory concentration of approximately 20 nM. VP32947 inhibits both cytopathic and noncytopathic pestiviruse...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.140220397

    authors: Baginski SG,Pevear DC,Seipel M,Sun SC,Benetatos CA,Chunduru SK,Rice CM,Collett MS

    更新日期:2000-07-05 00:00:00

  • Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation.

    abstract::Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that st...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2010722117

    authors: Cheng MH,Zhang S,Porritt RA,Noval Rivas M,Paschold L,Willscher E,Binder M,Arditi M,Bahar I

    更新日期:2020-10-13 00:00:00

  • The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments.

    abstract::Our recent studies have shown that deregulated expression of R2, the rate-limiting component of ribonucleotide reductase, enhances transformation and malignant potential by cooperating with activated oncogenes. We now demonstrate that the R1 component of ribonucleotide reductase has tumor-suppressing activity. Stable ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.24.13181

    authors: Fan H,Huang A,Villegas C,Wright JA

    更新日期:1997-11-25 00:00:00

  • Variable genetic architectures produce virtually identical molecules in bacterial symbionts of fungus-growing ants.

    abstract::Small molecules produced by Actinobacteria have played a prominent role in both drug discovery and organic chemistry. As part of a larger study of the actinobacterial symbionts of fungus-growing ants, we discovered a small family of three previously unreported piperazic acid-containing cyclic depsipeptides, gerumycins...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1515348112

    authors: Sit CS,Ruzzini AC,Van Arnam EB,Ramadhar TR,Currie CR,Clardy J

    更新日期:2015-10-27 00:00:00

  • Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation.

    abstract::Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1615413114

    authors: Rothhammer V,Kenison JE,Tjon E,Takenaka MC,de Lima KA,Borucki DM,Chao CC,Wilz A,Blain M,Healy L,Antel J,Quintana FJ

    更新日期:2017-02-21 00:00:00

  • Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage.

    abstract::A series of monoclonal antibodies was used to define three discrete stages of human intrathymic T-cell differentiation. The earliest stage was confined to <10% of thymocytes, which were.reactive with both OKT9 and OKT10. Subsequently, approximately 70% of human thymocytes acquired a thymocyte-restricted antigen, OKT6,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.3.1588

    authors: Reinherz EL,Kung PC,Goldstein G,Levey RH,Schlossman SF

    更新日期:1980-03-01 00:00:00

  • DNA inversion within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain patients with premature atherosclerosis.

    abstract::The genes coding for apolipoproteins (apo) AI, CIII, and AIV, designated APOA1, APOC3, and APOA4, respectively, are closely linked and tandemly organized in the long arm of the human chromosome 11. A DNA rearrangement involving the genes encoding apoAI and apoCIII in certain patients with premature atherosclerosis has...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.20.7198

    authors: Karathanasis SK,Ferris E,Haddad IA

    更新日期:1987-10-01 00:00:00

  • Use of synthetic oligonucleotides as hybridization probes: isolation of cloned cDNA sequences for human beta 2-microglobulin.

    abstract::We have synthesized two sets of 15-base-long oligodeoxyribonucleotides corresponding to all possible coding sequences for a small portion of human beta 2-microglobulin. Labeled oligonucleotides were used as hybridization probes to screen bacterial clones containing cDNA sequences primed with oligo(dT) and inserted int...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.11.6613

    authors: Suggs SV,Wallace RB,Hirose T,Kawashima EH,Itakura K

    更新日期:1981-11-01 00:00:00

  • Cultured melanocytes from dilute mutant mice exhibit dendritic morphology and altered melanosome distribution.

    abstract::Mutant alleles at the dilute unconventional myosin heavy chain locus cause diluted coat color, opisthotonic seizures, and death. The dilute coat color phenotype is caused by irregular clumping of pigment in the hair, but amounts of melanin are unchanged from wild-type controls. The melanocyte phenotype has been descri...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.25.14554

    authors: Provance DW Jr,Wei M,Ipe V,Mercer JA

    更新日期:1996-12-10 00:00:00

  • RNA polymerase II CTD interactome with 3' processing and termination factors in fission yeast and its impact on phosphate homeostasis.

    abstract::The carboxy-terminal domain (CTD) code encrypted within the Y1S2P3T4S5P6S7 heptad repeats of RNA polymerase II (Pol2) is deeply rooted in eukaryal biology. Key steps to deciphering the code are identifying the events in gene expression that are governed by individual "letters" and then defining a vocabulary of multile...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1810711115

    authors: Sanchez AM,Shuman S,Schwer B

    更新日期:2018-11-06 00:00:00

  • Allorecognition of purified major histocompatibility complex glycoproteins by cytotoxic T lymphocytes.

    abstract::To investigate how T cells recognize allogeneic class I proteins encoded by the major histocompatibility complex (MHC), we examined the human cytotoxic T lymphocytes (CTL) elicited in a mixed lymphocyte reaction against a lymphoblastoid B-cell line (JY) whose MHC-class I proteins are HLA-A2 and -B7. By panning the res...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.8.2728

    authors: Elliott TJ,Eisen HN

    更新日期:1988-04-01 00:00:00

  • Tracking footprints of maize domestication and evidence for a massive selective sweep on chromosome 10.

    abstract::Maize domestication is one of the greatest feats of artificial selection and evolution, wherein a weedy plant in Central Mexico was converted through human-mediated selection into the most productive crop in the world. In fact, the changes were so astounding that it took much of the last century to identify modern mai...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章,评审

    doi:10.1073/pnas.0901122106

    authors: Tian F,Stevens NM,Buckler ES 4th

    更新日期:2009-06-16 00:00:00

  • Regulation of p53 tetramerization and nuclear export by ARC.

    abstract::Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0710017104

    authors: Foo RS,Nam YJ,Ostreicher MJ,Metzl MD,Whelan RS,Peng CF,Ashton AW,Fu W,Mani K,Chin SF,Provenzano E,Ellis I,Figg N,Pinder S,Bennett MR,Caldas C,Kitsis RN

    更新日期:2007-12-26 00:00:00

  • A 40-base-pair sequence in the 3' end of the beta-actin gene regulates beta-actin mRNA transcription during myogenesis.

    abstract::In an earlier report, evidence was presented that the down-regulation of beta-actin mRNA during myogenesis was controlled by a region 3' to the promoter of the gene. In this paper we report the location of this regulatory sequence, determined by deletion analysis and the use of chimeric genes, transfected stably into ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.5.1389

    authors: DePonti-Zilli L,Seiler-Tuyns A,Paterson BM

    更新日期:1988-03-01 00:00:00

  • Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties.

    abstract::Phosphorylation is a major mechanism regulating the activity of ion channels that remains poorly understood with respect to T-type calcium channels (Cav3). These channels are low voltage-activated calcium channels that play a key role in cellular excitability and various physiological functions. Their dysfunction has ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1511740112

    authors: Blesneac I,Chemin J,Bidaud I,Huc-Brandt S,Vandermoere F,Lory P

    更新日期:2015-11-03 00:00:00

  • Mechanism of epidermal growth factor receptor autophosphorylation and high-affinity binding.

    abstract::Epidermal growth factor (EGF) receptor monomers and noncovalently associated dimers were isolated by sucrose density gradient centrifugation, and their respective binding and autophosphorylation activities were determined. We find that monomers are low-affinity receptors and dimers are high-affinity receptors. In the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.22.7832

    authors: Böni-Schnetzler M,Pilch PF

    更新日期:1987-11-01 00:00:00

  • Catalysis of amide synthesis by RNA phosphodiester and hydroxyl groups.

    abstract::The functional groups found among the RNA bases and in the phosphoribose backbone represent a limited repertoire from which to construct a ribozyme active site. This work investigates the possibility that simple RNA phosphodiester and hydroxyl functional groups could catalyze amide bond synthesis. Reaction of amine gr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.212527799

    authors: Chamberlin SI,Merino EJ,Weeks KM

    更新日期:2002-11-12 00:00:00

  • Regulation of the threonine operon: tandem threonine and isoleucine codons in the control region and translational control of transcription termination.

    abstract::The DNA sequence of 178 base pairs preceding the first structural gene of the threonine operon of Escherichia coli has been determined. A region of perfect 2-fold rotational symmetry, involving 28 base pairs, precedes the first structural gene. The structural similarity of this sequence to known RNA polymerase termina...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.4.1706

    authors: Gardner JF

    更新日期:1979-04-01 00:00:00

  • Isolation of circular DNA molecules from whole cellular DNA by use of ATP-dependent deoxyribonuclease.

    abstract::A technique is described for isolation of plasmid DNA in closed and open circular double-stranded forms from bacterial cells, by use of ATP-dependent deoxyribonuclease purified from Micrococcus luteus. This DNase, acting only upon linear DNA molecules, degrades all bacterial chromosomal DNA extracted in the linear for...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.70.10.2884

    authors: Mukai T,Matsubara K,Takagi Y

    更新日期:1973-10-01 00:00:00

  • Galphai generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts.

    abstract::Drosophila neuroblasts divide asymmetrically by aligning their mitotic spindle with cortical cell polarity to generate distinct sibling cell types. Neuroblasts asymmetrically localize Galphai, Pins, and Mud proteins; Pins/Galphai direct cortical polarity, whereas Mud is required for spindle orientation. It is currentl...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0701812104

    authors: Nipper RW,Siller KH,Smith NR,Doe CQ,Prehoda KE

    更新日期:2007-09-04 00:00:00

  • Cryoelectron microscopy of lambda phage DNA condensates in vitreous ice: the fine structure of DNA toroids.

    abstract::DNA toroids produced by the condensation of lambda phage DNA with hexammine cobalt (III) have been investigated by cryoelectron microscopy. Image resolution obtained by this technique has allowed unprecedented views of DNA packing within toroidal condensates. Toroids oriented coplanar with the microscope image plane e...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.261560398

    authors: Hud NV,Downing KH

    更新日期:2001-12-18 00:00:00

  • Functional mapping of disease susceptibility loci using cell biology.

    abstract::In most genome-wide linkage studies, implication of a causative disease gene often requires years of expanding the study to more families and finer mapping of the initially described region. Even after such efforts, unobtainable sample sizes can be required to make statistically meaningful conclusions about a single g...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0510521103

    authors: Antinozzi PA,Garcia-Diaz A,Hu C,Rothman JE

    更新日期:2006-03-07 00:00:00

  • Operant matching is a generic outcome of synaptic plasticity based on the covariance between reward and neural activity.

    abstract::The probability of choosing an alternative in a long sequence of repeated choices is proportional to the total reward derived from that alternative, a phenomenon known as Herrnstein's matching law. This behavior is remarkably conserved across species and experimental conditions, but its underlying neural mechanisms st...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0505220103

    authors: Loewenstein Y,Seung HS

    更新日期:2006-10-10 00:00:00

  • Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors.

    abstract::The inositol 1,4,5-trisphosphate receptor (IP3R) in the endoplasmic reticulum mediates calcium signaling that impinges on intracellular processes. IP3Rs are allosteric proteins comprising four subunits that form an ion channel activated by binding of IP3 at a distance. Defective allostery in IP3R is considered crucial...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1409730111

    authors: Hamada K,Terauchi A,Nakamura K,Higo T,Nukina N,Matsumoto N,Hisatsune C,Nakamura T,Mikoshiba K

    更新日期:2014-09-23 00:00:00

  • Scrapie-associated prion protein accumulates in astrocytes during scrapie infection.

    abstract::In the course of scrapie, a transmissible spongiform encephalopathy caused by an unconventional agent, a normal cellular protein is converted to an abnormal form that copurifies with infectivity and aggregates to form deposits of amyloid. We have used immunocytochemistry and methods that enhance detection of amyloidog...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.2.375

    authors: Diedrich JF,Bendheim PE,Kim YS,Carp RI,Haase AT

    更新日期:1991-01-15 00:00:00

  • Mapping methyl jasmonate-mediated transcriptional reprogramming of metabolism and cell cycle progression in cultured Arabidopsis cells.

    abstract::Jasmonates (JAs) are plant-specific signaling molecules that steer a diverse set of physiological and developmental processes. Pathogen attack and wounding inflicted by herbivores induce the biosynthesis of these hormones, triggering defense responses both locally and systemically. We report on alterations in the tran...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0711203105

    authors: Pauwels L,Morreel K,De Witte E,Lammertyn F,Van Montagu M,Boerjan W,Inzé D,Goossens A

    更新日期:2008-01-29 00:00:00

  • Linkage mapping of a mouse gene, iv, that controls left-right asymmetry of the heart and viscera.

    abstract::Inherited single gene defects have been identified in both humans and mice that lead to loss of developmental control over the left-right asymmetry of the heart and viscera. In mice the recessively inherited mutation iv leads to such apparent loss of control over situs: 50% of iv/iv mice exhibit situs inversus and 50%...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.13.5035

    authors: Brueckner M,D'Eustachio P,Horwich AL

    更新日期:1989-07-01 00:00:00

  • Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia.

    abstract::Morphine produces analgesia at opiate receptors expressed in nociceptive circuits. mu, delta, and kappa opiate receptor subtypes are expressed in circuits that can modulate nociception and receive inputs from endogenous opioid neuropeptide ligands. The roles played by each receptor subtype in nociceptive processing in...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.4.1544

    authors: Sora I,Takahashi N,Funada M,Ujike H,Revay RS,Donovan DM,Miner LL,Uhl GR

    更新日期:1997-02-18 00:00:00

  • Annexin 2-caveolin 1 complex is a target of ezetimibe and regulates intestinal cholesterol transport.

    abstract::Modulation of cholesterol absorption in the intestine, the primary site of dietary cholesterol uptake in humans, can have profound clinical implications. We have undertaken a reverse genetic approach by disrupting putative cholesterol processing genes in zebrafish larvae by using morpholino (MO) antisense oligonucleot...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章,收录出版

    doi:10.1073/pnas.0400441101

    authors: Smart EJ,De Rose RA,Farber SA

    更新日期:2004-03-09 00:00:00

  • Linking global climate and temperature variability to widespread amphibian declines putatively caused by disease.

    abstract::The role of global climate change in the decline of biodiversity and the emergence of infectious diseases remains controversial, and the effect of climatic variability, in particular, has largely been ignored. For instance, it was recently revealed that the proposed link between climate change and widespread amphibian...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0912883107

    authors: Rohr JR,Raffel TR

    更新日期:2010-05-04 00:00:00