Chromatin, Epigenetics, Genomics & Functional Genomics
- Specific but interdependent functions for Arabidopsis AGO4 and AGO6 in RNA‐directed DNA methylation
- Cheng‐Guo Duan1,†,
- Huiming Zhang1,†,
- Kai Tang1,†,
- Xiaohong Zhu1,
- Weiqiang Qian2,
- Yueh‐Ju Hou1,
- Bangshing Wang1,
- Zhaobo Lang1,
- Yang Zhao1,2,
- Xingang Wang1,
- Pengcheng Wang1,
- Jianping Zhou3,
- Gaimei Liang4,
- Na Liu5,
- Chunguo Wang6 and
- Jian‐Kang Zhu*,1,2
- 1Department of Horticulture and Landscape Architecture, Purdue University, West Lafayette, IN, USA
- 2Shanghai Center for Plant Stress Biology, Shanghai Institute of Biological Sciences Chinese Academy of Sciences, Shanghai, China
- 3School of Life Science and Technology University of Electronic Science and Technology of China, Chengdu Sichuan, China
- 4Dryland Agriculture Research Center, Shanxi Academy of Agricultural Sciences, Taiyuan Shanxi, China
- 5Department of Horticulture, Laboratory of Genetics Resources & Functional Improvement for Horticultural Plant Zhejiang University, Hangzhou Zhejiang, China
- 6College of Life Sciences Nankai University, Tianjin, China
- ↵*Corresponding author. Tel: +1 765 4967601; E‐mail: jkzhu{at}purdue.edu
↵† These authors contribute equally
AGO4 and AGO6 have distinct, but cooperative functions in RNA‐directed DNA methylation in Arabidopsis and show spatially segregated interactions with RNA polymerases II and V, respectively.
Synopsis
AGO4 and AGO6 have distinct, but cooperative functions in RNA‐directed DNA methylation in Arabidopsis and show spatially segregated interactions with RNA polymerases II and V, respectively.
Genome‐wide DNA methylation analysis reveals that AGO4 and AGO6 are mutually required in the majority of AGO4‐ and AGO6‐dependent methylated loci;
AGO4 and AGO6 display different co‐localization patterns with DNA‐dependent RNA polymerase;
RNA Pol II physically interacts with AGO4 but not AGO6;
RNA Pol V chromatin occupancy and the accumulation of Pol V‐dependent scaffold RNAs requires AGO6 but not AGO4
The EMBO Journal (2015) 34: 581–592
- Received July 5, 2014.
- Revision received November 25, 2014.
- Accepted November 28, 2014.
- © 2014 The Authors
- Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR‐SET7‐deficient livers
- Kostas C Nikolaou1,
- Panagiotis Moulos1,
- George Chalepakis2,
- Pantelis Hatzis1,
- Hisanobu Oda3,4,
- Danny Reinberg5 and
- Iannis Talianidis*,1
- 1Biomedical Sciences Research Center Al. Fleming, Vari, Greece
- 2Department of Biology University of Crete, Herakleion, Greece
- 3Medical Institute of Bioregulation Kyusyu University, Fukuoka, Japan
- 4Gastrointestinal and Oncology Division, National Kyusyu Cancer Center, Fukuoka, Japan
- 5HHMI, Department of Biochemistry, New York University School of Medicine, New York, NY USA
- ↵*Corresponding author. Tel: +30 210 9653773; E‐mail: talianidis{at}fleming.gr
DNA damage, necrosis and inflammation caused by loss of the histone methyltransferase PR‐SET7 in adult mouse hepatocytes triggers compensatory activation of resident ductal progenitor cells, culminating in hepatocellular carcinoma.
Synopsis
Loss of the histone H4 lysine 20 mono‐methyltransferase PR‐SET7 in adult mouse hepatocytes causes DNA damage and necrotic cell death followed by tissue inflammation, fibrosis and ROS accumulation. Subsequent aberrant compensatory proliferation of resident progenitor cells with ductal markers elicits the development of hepatocellular carcinoma, providing insights into the controversial origin of hepatic cancer stem cells.
Proliferating PR‐SET7‐deficient adult mouse hepatocytes die via necrosis.
PR‐SET7‐deficient livers develop hepatocellular carcinoma.
The tumors are composed of cells with cancer stem cell (CSC) features.
Hepatic CSCs express ductal progenitor markers and re‐express hepatic oncofetal genes (factors that are usually expressed during fetal liver development).
The EMBO Journal (2015) 34: 430–447
- Received June 16, 2014.
- Revision received November 5, 2014.
- Accepted November 11, 2014.
- © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- RNA polymerase II contributes to preventing transcription‐mediated replication fork stalls
- 1Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Seville, Spain
- ↵*Corresponding author. Tel: +34 954468372; E‐mail: aguilo{at}us.es
Identification of specific yeast RNA polymerase II mutations that cause genomic instability by enhancing collisions with the DNA replication machinery suggests that eukaryotic RNAP II is more than a passive entity in the management of transcription–replication encounters.
Synopsis
Collisions between RNA transcription and DNA replication machineries impair replication fork (RF) progression and cause DNA breaks, demanding homologous recombination for repair and RF restart. Identification and characterization of specific yeast RNA polymerase II mutations that enhance DNA RF stalling and trigger hyper‐recombination suggests that increased RNAP II retention at transcription sites may contribute to genomic instability and that eukaryotic RNAP II is more than a passive entity in the management of transcription–replication encounters.
Specific RNAP II mutants in Saccharomyces cerevisiae, rpb1‐1, rpb1S71F and rbp9Δ show an increase in genetic instability as detected by hyper‐recombination, DNA damage sensitivity, and dependency on DSB repair functions for viability.
Impaired RF progression in these RNAP II mutants can be compensated by additional origin firing.
Under replication stress, checkpoint‐activating DNA lesions accumulate in these mutant cells and are repaired only with considerable delay.
RNase H1 overexpression does not suppress genome instability in rpb1 mutants, indicating that an increase in R‐loops is not a main determinant of RF stalling.
The causative rpb1‐1 mutation increases retention of RNAP II at the site of transcription.
The EMBO Journal (2015) 34: 236–250
- Received March 20, 2014.
- Revision received September 29, 2014.
- Accepted October 8, 2014.
- © 2014 The Authors
- A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity
- Dong‐Hyun Kim1,
- Zhen Xiao2,
- Sanghoon Kwon1,
- Xiaoxiao Sun3,
- Daniel Ryerson1,
- David Tkac1,
- Ping Ma3,
- Shwu‐Yuan Wu4,
- Cheng‐Ming Chiang4,
- Edward Zhou5,
- H Eric Xu5,
- Jorma J Palvimo6,
- Lin‐Feng Chen7,
- Byron Kemper1 and
- Jongsook Kim Kemper*,1
- 1Department of Molecular and Integrative Physiology, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
- 2Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC‐Frederick, Inc. National Cancer Institute‐Frederick, Frederick, MD, USA
- 3Department of Statistics, University of Georgia, Athens, GA, USA
- 4Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX, USA
- 5Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI, USA
- 6Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
- 7Department of Biochemistry, University of Illinois, Urbana, IL, USA
- ↵*Corresponding author. Tel: +1 217 333 6317; Fax: +1 217 333 1133; E‐mail: jongsook{at}illinois.edu
Elevated acetylation of the mouse nuclear Farnesoid X receptor (FXR) in obesity inhibits its SUMOylation, which promotes hepatic inflammation and metabolic dysfunction in vivo.
Synopsis
Acetylation levels of many transcriptional regulators are aberrantly elevated in obesity but the functional consequences are unclear. Elevated acetylation of the mouse nuclear Farnesoid X receptor (FXR) in obesity is found to inhibit its SUMOylation, constituting a molecular switch that promotes hepatic inflammation and metabolic dysfunction in vivo.
Agonist‐activated FXR is SUMO2‐modified at lysine 277 by the PIASy SUMO E3 ligase.
FXR SUMOylation inhibits inflammatory gene expression upon inflammatory signaling.
Selective inflammatory gene trans‐repression results from increased NF‐κB and decreased RXRα interaction of SUMO2‐FXR.
In obese mice, FXR acetylation at lysine 217 inhibits its SUMOylation and diminishes SUMO2‐dependent FXR anti‐inflammatory action.
The EMBO Journal (2015) 34: 184–199
- Received July 15, 2014.
- Revision received September 15, 2014.
- Accepted October 8, 2014.
- © 2014 The Authors
- Fission yeast Cactin restricts telomere transcription and elongation by controlling Rap1 levels
- Luca E Lorenzi1,
- Amadou Bah1,
- Harry Wischnewski1,
- Vadim Shchepachev1,
- Charlotte Soneson2,
- Marco Santagostino3 and
- Claus M Azzalin*,1
- 1Institute of Biochemistry (IBC) Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich, Switzerland
- 2Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
- 3Dipartimento di Biologia e Biotecnologie “L. Spallanzani”, Università degli Studi di Pavia, Pavia, Italy
- ↵*Corresponding author. Tel: +41 44 633 4410; Fax: +41 44 632 1298; E‐mail: claus.azzalin{at}bc.biol.ethz.ch
Cactin emerges from a genomewide screen for factors controlling telomeric transcription, regulating Rap1 expression both on the level of splicing efficiency and protein stability.
Synopsis
Cactin emerges from a genomewide screen for factors controlling telomeric transcription, regulating Rap1 expression both on the level of splicing efficiency and protein stability.
Fission yeast Cay1 promotes Rap1 pre‐mRNA splicing and protein stability.
Reduced Rap1 levels in cay1∆ cells lead to accumulation of acetylated H3K9 at telomeres, telomere desilencing, and telomere elongation.
Abnormal telomeres in cay1∆ cells cause chromosomal aberrations in the cold.
cay1∆ cells accumulate unprocessed retrotransposon Tf2 transcripts independently of Rap1.
The EMBO Journal (2015) 34: 115–129
- Received July 18, 2014.
- Revision received October 19, 2014.
- Accepted October 20, 2014.
- © 2014 The Authors
- ARGONAUTE 6 bridges transposable element mRNA‐derived siRNAs to the establishment of DNA methylation
- Andrea D McCue1,
- Kaushik Panda1,
- Saivageethi Nuthikattu1,
- Sarah G Choudury1,
- Erica N Thomas1 and
- R Keith Slotkin*,1
- ↵*Corresponding author. Tel: +1 614 292 1087; E‐mail: Slotkin.2{at}OSU.edu
Transcriptional activation of transposable elements (TEs) in plants leads to initial mRNA destruction through RNAi. AGO6 incorporates the resulting siRNAs and induces DNA methylation at TE target loci, thus establishing de novo epigenetic silencing.
Synopsis
Transcriptional activation of transposable elements (TEs) in plants leads to initial mRNA destruction through RNAi. AGO6 incorporates the resulting siRNAs and induces DNA methylation at TE target loci, thus establishing de novo epigenetic silencing.
RNA‐directed DNA methylation targets transcriptionally active transposable elements
AGO6 incorporates 21–22nt siRNAs produced by RNAi from transposable element mRNAs
Transposon‐derived siRNAs target AGO6 to chromatin and direct de novo DNA methylation
AGO6 plays a dual role by maintaining epigenetic silencing and initiating establishment of repressive chromatin states
This mechanism bridges the worlds of post‐transcriptional and transcriptional gene silencing by linking mRNA degradation via RNAi to the establishment of DNA methylation
The EMBO Journal (2015) 34: 20–35
- Received July 10, 2014.
- Revision received September 30, 2014.
- Accepted October 6, 2014.
- © 2014 The Authors
- Shigella hacks host immune responses by reprogramming the host epigenome
Bacterial pathogens alter host transcriptional programs to promote infection. Shigella OspF is an essential virulence protein with a unique phosphothreonine lyase activity. A new study in The EMBO Journal (Harouz et al, 2014) reveals a novel function of OspF: targeting of heterochromatin protein 1γ (HP1γ) and downregulation of a subset of immune genes. These results illustrate how bacterial pathogens exploit epigenetic modifications to counteract host immune responses.
See also: H Harouz et al (November 2014)
During infection, Shigella injects effector protein OspF to modulate the epigenetic status of specific host genes. This effect involves dual targeting of both histones and the chromatin reader HP1γ.
- © 2014 The Authors
- Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF
- Habiba Harouz1,†,
- Christophe Rachez2,3,†,
- Benoit M Meijer1,
- Benoit Marteyn1,
- Françoise Donnadieu1,
- Florence Cammas4,
- Christian Muchardt2,3,
- Philippe Sansonetti1 and
- Laurence Arbibe*,15
- 1Unité de Pathogénie Microbienne Moléculaire, Unité INSERM 786 Institut Pasteur, Paris, France
- 2Department of Biologie du Développement et Cellules Souches, Unité de Régulation Epigénétique, Institut Pasteur, Paris, France
- 3URA2578 CNRS, Paris, France
- 4Equipe Epigénétique, différenciation cellulaire et cancer IRCM, Montpellier, France
- 5Equipe plasticité du génome et infection, Institut Necker‐Enfants Malades INSERM U1151 CNRS UMR 8253 Université Paris Descartes, Paris, France
- ↵*Corresponding author. Tel: +33 1 72606430; Fax: +33 1 72606401; E‐mail: laurence.arbibe{at}inserm.fr
-
↵† These two authors contributed equally
The Shigella virulence effector OspF regulates the activity and phosphorylation status of the chromatin reader HP1γ by inactivating the HP1γ kinase MSK1.
Synopsis
HP1γ functions as an epigenetic regulator of a series of innate immune genes and, as such, its phosphorylation status is targeted by the phosphothreonine lyase OspF from the bacterial pathogen Shigella flexneri.
In the colon, the non‐invasive proinflammatory mxiD Shigella mutant causes considerably more HP1γ phosphorylation than wild‐type Shigella.
The Shigella virulence effector OspF directly interacts with HP1γ and causes its dephosphorylation at S83 by inactivating the Erk‐MSK1 nuclear signaling pathway.
The MSK1 kinase arises as a new HP1 kinase phosphorylating HP1γ at S83 and allowing for HP1 accumulation at transcriptionally active immune genes.
OspF impairs HP1γ accumulation at immune genes and thereby uncouples transcriptional activation from recruitment of HP1γ.
HP1γ fine‐tunes the transcriptional response of immune genes while also up‐regulating proliferative genes, suggesting its implication in both defense and repair of the mucosa in response to infectious challenges.
The EMBO Journal (2014) 33: 2606–2622
- Received June 10, 2014.
- Revision received July 31, 2014.
- Accepted August 4, 2014.
- © 2014 The Authors
- Determinants of G quadruplex‐induced epigenetic instability in REV1‐deficient cells
- Davide Schiavone1,†,
- Guillaume Guilbaud1,†,
- Pierre Murat2,
- Charikleia Papadopoulou1,
- Peter Sarkies1,3,
- Marie‐Noëlle Prioleau4,
- Shankar Balasubramanian2 and
- Julian E Sale*,1
- 1Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
- 2Department of Chemistry, University of Cambridge, Cambridge, UK
- 3The Gurdon Institute, Cambridge, UK
- 4Institut Jacques Monod, Université Paris Diderot‐Paris 7, Paris, France
- ↵*Corresponding author. Tel: +44 1223 267099; E‐mail: jes{at}mrc-lmb.cam.ac.uk
-
↵† These authors contributed equally to this work
Maintenance of ‘active’ histone modification patterns and gene expression at an endogenous reporter gene locus requires its processive replication, being affected by G4 DNA formation on the leading strand template close to the transcription start site.
Synopsis
G quadruplex (G4)‐forming DNA can lead to replication‐dependent, localised loss of histone modifications and changes in gene expression in chicken DT40 cells lacking the specialised DNA polymerase REV1. Determinants of this epigenetic instability, identified using the cell surface gene Bu‐1 as a reporter, indicate that processive replication is required to maintain the histone modification pattern and active expression of this gene locus.
Epigenetic instability at the Bu‐1 gene locus depends on a single G4 motif located 3.5 kb downstream of the transcription start site (TSS).
Epigenetic instability requires G4 formation on the leading strand template of a replication fork heading toward the TSS.
G4 ability to cause epigenetic instability in the absence of REV1 does not correlate with G4 in vitro thermal stability, but with predicted intra‐G4 loop length.
G4 motif position directly affects the pattern of ‘active’ histone modifications around the TSS, with expression being reduced only when the promoter is affected.
The EMBO Journal (2014) 33: 2507–2520
- Received March 5, 2014.
- Revision received July 23, 2014.
- Accepted August 13, 2014.
- © 2014 MRC Laboratory of Molecular Biology. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Akirin specifies NF‐κB selectivity of Drosophila innate immune response via chromatin remodeling
- François Bonnay1,†,
- Xuan‐Hung Nguyen1,†,
- Eva Cohen‐Berros1,
- Laurent Troxler1,
- Eric Batsche2,
- Jacques Camonis3,
- Osamu Takeuchi4,
- Jean‐Marc Reichhart1 and
- Nicolas Matt*,1
- 1UPR9022 du CNRS, Institut de Biologie Moléculaire et Cellulaire Université de Strasbourg, Strasbourg Cedex, France
- 2Département de Biologie du Développement, Institut Pasteur, CNRS URA2578, Unité de Régulation Epigénétique, Paris, France
- 3Institut Curie INSERM U‐528, Paris Cedex, France
- 4Laboratory of Infection and Prevention, Institute for Virus Research Kyoto University CREST, JST, Sakyo‐ku, Kyoto, Japan
- ↵*Corresponding author. Tel: +33 388 417 089; Fax: +33 388 606 922; E‐mail: n.matt{at}unistra.fr
-
↵† These authors contributed equally to this work
The nuclear factor Akirin orchestrates NF‐κB transcriptional selectivity through the recruitment of the Osa‐containing‐SWI/SNF Brahma complex (BAP), by activating a subset of NF‐κB effector genes.
Synopsis
The nuclear factor Akirin orchestrates NF‐κB transcriptional selectivity through the recruitment of the Osa‐containing‐SWI/SNF Brahma complex (BAP), by activating a subset of NF‐κB effector genes.
In the Drosophila innate immune response, Akirin is required for NF‐κB selectivity.
Akirin interacts with the SWI/SNF Bap60 subunit upon immune challenge.
Akirin promotes SWI/SNF (BAP)‐dependent activation of a subset of immuno‐induced genes.
Relish, Akirin and Bap60 are recruited on a subset of NF‐κB‐dependent promoters.
SWI/SNF‐like (BAP) complex is required for fly defense against Gram‐negative bacteria.
The EMBO Journal (2014) 33: 2349–2362
- Received March 10, 2014.
- Revision received August 7, 2014.
- Accepted August 8, 2014.
- © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
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