Chromatin, Epigenetics, Genomics & Functional Genomics
- BRPF3‐HBO1 regulates replication origin activation and histone H3K14 acetylation
- Yunpeng Feng1,8,†,
- Arsenios Vlassis1,†,
- Céline Roques2,†,
- Marie‐Eve Lalonde2,
- Cristina González‐Aguilera1,
- Jean‐Philippe Lambert3,
- Sung‐Bau Lee1,4,
- Xiaobei Zhao5,9,
- Constance Alabert1,
- Jens V Johansen1,
- Eric Paquet2,
- Xiang‐Jiao Yang6,
- Anne‐Claude Gingras3,7,
- Jacques Côté*,2 and
- Anja Groth*,1
- 1Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark
- 2St‐Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Axis‐CHU de Québec Research Center, Quebec City, QC, Canada
- 3Lunenfeld‐Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- 4Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- 5Bioinformatics Centre Department of Biology, University of Copenhagen, Copenhagen, Denmark
- 6Department of Medicine, McGill University Health Center, Montréal, QC, Canada
- 7Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- 8The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China
- 9Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
- ↵*
Corresponding author. Tel: +1 418 525 4444, poste 15545; E‐mail: jacques.cote{at}crhdq.ulaval.ca
Corresponding author. Tel: +45 3532 5538; E‐mail: anja.groth{at}bric.ku.dk
↵† These authors contributed equally to this work
An RNAi screen for chromatin regulators of replication control reveals an origin activation role of HBO1 acetyltransferase role that is separate from its function in origin licensing.
Synopsis
A distinct origin activation role of HBO1 acetyltransferase provides new insight into how demarcation of chromatin surrounding transcription start sites affects the regulation of nearby replication origins.
siRNA screen identifies chromatin regulators important for DNA replication, including the scaffold protein BRPF3.
BRPF3 regulates origin firing by directing the acetyltransferase HBO1 to target histone H3K14 in chromatin surrounding replication origins.
HBO1‐BRPF3 complex function in origin activation is separate from and complementary to HBO1‐JADE1 function in origin licensing.
Reduced origin activation upon BRPF3 depletion protects cells against replication stress‐induced DNA damage.
The EMBO Journal (2016) 35: 176–192
- Received February 16, 2015.
- Revision received October 30, 2015.
- Accepted November 3, 2015.
- © 2015 The Authors
- Putting chromatin in its place: the pioneer factor NeuroD1 modulates chromatin state to drive cell fate decisions
Cell fate decisions require the deployment of distinct transcriptional programmes—how this is controlled and orchestrated is a key question from basic developmental biology to regenerative medicine. In this issue of The EMBO Journal, Pataskar and Jung et al (Pataskar et al, 2015) demonstrate how the transcription factor NeuroD1 acts genome‐wide to elicit a specific neurogenic programme, including differentiation and migration. Much of that activity is due to NeuroD1 acting as a pioneer factor. NeuroD1 is able to bind its targets within repressive chromatin and can induce a more open chromatin state amenable to cell type‐specific regulation.
See also: A Pataskar et al (January 2016)
New work illustrates how transcription factor NeuroD1 reshapes the chromatin landscape to elicit a specific neurogenic program and drive cells down a distinct differentiation pathway.
- © 2015 The Authors
- NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program
- Abhijeet Pataskar1,†,
- Johannes Jung1,†,
- Pawel Smialowski2,
- Florian Noack3,
- Federico Calegari3,
- Tobias Straub2 and
- Vijay K Tiwari*,1
- 1Institute of Molecular Biology (IMB), Mainz, Germany
- 2Adolf Butenandt Institute and Center for Integrated Protein Science, Ludwig Maximilian University, Munich, Germany
- 3DFG‐Research Center for Regenerative Therapies, Cluster of Excellence, TU‐Dresden, Dresden, Germany
- ↵*Corresponding author. Tel: +49 6131 39 21460; E‐mail: v.tiwari{at}imb-mainz.de
↵† These authors contributed equally to this work
Using a genome‐wide approach this study delineates the binding requirements and target sites for NeuroD1, illustrating how this factor drives the formation of a transcriptional and epigenetic program to ensure neuronal differentiation.
Synopsis
Using a genome‐wide approach this study delineates the binding requirements and target sites for NeuroD1, illustrating how this factor drives the formation of a transcriptional and epigenetic program to ensure neuronal differentiation.
Genome‐wide assessment of NeuroD1 binding reveals its targeting to regulatory elements of critical neuronal development genes.
Following expression, NeuroD1 locates to and binds its target genomic locations in a highly sequence‐specific fashion.
Prior to NeuroD1 binding, its target sites are developmentally silenced by epigenetic mechanisms and regulatory factors.
NeuroD1 binding initiates events that confer transcriptional competence to neuronal fate genes including conversion of heterochromatin to euchromatin and reprogramming of the transcription factor landscape.
The transient action of NeuroD1 during neuronal development is sufficient to induce a neuronal gene expression program that is maintained by epigenetic mechanisms.
The EMBO Journal (2016) 35: 24–45
- Received February 6, 2015.
- Revision received August 31, 2015.
- Accepted September 14, 2015.
- © 2015 The Authors
- Assembly of the nucleolus: in need of revision
- Maria Carmo‐Fonseca (carmo.fonseca{at}medicina.ulisboa.pt)1
Our current view of the nucleolus has been shaped by the concept that the organization of this prominent compartment within the nucleus is primarily dictated by its function, the making of ribosome subunits. Whether ribosome biogenesis is framed by a dedicated nucleolar scaffold has remained unclear. In this issue of The EMBO Journal, Caudron‐Herger and colleagues present evidence for a nucleolar skeleton composed of non‐coding RNA enriched in Alu repeat elements.
See also: M Caudron‐Herger et al (November 2015)
A new study identifies a role for intron‐derived Alu elements in scaffolding the assembly of the nucleolus, thus shedding light on an abundant group of non‐coding RNAs.
- © 2015 The Author
- Alu element‐containing RNAs maintain nucleolar structure and function
- Maïwen Caudron‐Herger*,1,
- Teresa Pankert1,
- Jeanette Seiler2,
- Attila Németh3,
- Renate Voit2,
- Ingrid Grummt2 and
- Karsten Rippe*,1
- 1Genome Organization & Function, German Cancer Research Center (DKFZ) Bioquant Center, Heidelberg, Germany
- 2Molecular Biology of the Cell II, German Cancer Research Center, Heidelberg, Germany
- 3Department of Biochemistry III, Biochemistry Center Regensburg University of Regensburg, Regensburg, Germany
- ↵*
Corresponding author. Tel: +49 6221 5451373; E‐mail: m.caudron{at}dkfz.de
Corresponding author. Tel: +49 6221 5451376; E‐mail: karsten.rippe{at}dkfz.de
The human genome encodes thousands of Alu repeats of unclear function. This study shows intronic Alu elements transcribed by RNA Pol II to be enriched in the nucleolus where they maintain nucleolar integrity and ensure pre‐rRNA synthesis.
Synopsis
The human genome encodes thousands of Alu repeats of unclear function. This study shows intronic Alu elements transcribed by RNA Pol II to be enriched in the nucleolus where they maintain nucleolar integrity and ensure pre‐rRNA synthesis.
Intronic Alu element‐containing RNAs (aluRNAs) are enriched in the nucleolus.
Depletion of aluRNAs disrupts nucleolar structure and impairs rRNA production, while overexpression of aluRNAs increases both nucleolus size and rRNA levels.
aluRNAs interact with nucleolin and can target large genomic loci to the nucleolus.
aluRNAs are produced by RNA polymerase II and link its activity to rRNA production by RNA polymerase I.
The EMBO Journal (2015) 34: 2758–2774
- Received March 6, 2015.
- Revision received August 25, 2015.
- Accepted August 31, 2015.
- © 2015 The Authors
- H3K9 methylation extends across natural boundaries of heterochromatin in the absence of an HP1 protein
- Rieka Stunnenberg1,2,
- Raghavendran Kulasegaran‐Shylini1,3,
- Claudia Keller1,2,4,
- Moritz A Kirschmann1,5,
- Laurent Gelman1 and
- Marc Bühler*,1,2
- 1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- 2University of Basel, Basel, Switzerland
- 3Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, UK
- 4 Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- 5 Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland
- ↵*Corresponding author. Tel: +41 61 696 04 38; E‐mail: marc.buehler{at}fmi.ch
Originally thought to be a stably bound protein required for heterochromatin formation, this study shows that HP1/Swi6 is highly dynamic and rather acts to prevent unwanted propagation of a silenced epigenetic state.
Synopsis
Originally thought to be a stably bound protein required for heterochromatin formation, this study shows that HP1/Swi6 is highly dynamic and rather acts to prevent unwanted propagation of a silenced epigenetic state.
HP1/Swi6 exists as a single highly dynamic population that rapidly exchanges in cis and in trans between different heterochromatin domains.
Heterochromatin is permissive for transcription throughout the entire cell cycle in fission yeast.
Removal of RNA from HP1/Swi6 constitutes a rate‐limiting step in the HP1/Swi6 exchange cycle.
HP1/Swi6 dimers can constrain the propagation of H3K9 methylation.
Polymerization of Tas3, a member of the RNA‐induced transcriptional silencing (RITS) complex, is crucial to maintaining centromeric heterochromatin in the absence of HP1/Swi6.
The EMBO Journal (2015) 34: 2789–2803
- Received February 17, 2015.
- Revision received August 28, 2015.
- Accepted September 3, 2015.
- © 2015 The Authors. 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.
- MED23: a new Mediator of H2B monoubiquitylation
The Mediator multiprotein complex physically links transcription factors to RNA polymerase II and the basal transcription machinery. While the Mediator complex has been shown to be required for transcriptional initiation and elongation, the understanding of its interplay with histone modifying enzymes and post‐translational modifications remains elusive. In this issue of The EMBO Journal, Yao et al (2015) report that the MED23 subunit of the Mediator complex physically associates with the heterodimeric RNF20/40 E3‐ligase complex to facilitate the monoubiquitylation of histone H2B on gene bodies of actively transcribed genes.
See also: X Yao et al (December 2015)
New work reports a specific role for a subunit of the Mediator complex in stimulating histone modifications in actively transcribed genes via the recruitment of RNF20/40.
- © 2015 The Authors
- The Mediator subunit MED23 couples H2B mono‐ubiquitination to transcriptional control and cell fate determination
- Xiao Yao1,
- Zhanyun Tang2,
- Xing Fu3,
- Jingwen Yin1,
- Yan Liang1,
- Chonghui Li1,
- Huayun Li1,
- Qing Tian1,
- Robert G Roeder2 and
- Gang Wang*,1
- 1State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China
- 2Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA
- 3Shanghai Center for Plant Stress Biology, Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China
- ↵*Corresponding author. Tel: +86 021 54921083; E‐mail: gwang{at}sibcb.ac.cn
The Mediator subunit MED23 regulates histone 2B mono‐ubiquitylation via RNF20/40 recruitment, leading to transcriptional activation of target genes and illustrating a role for MED23 in myogenesis and tumorigenesis.
Synopsis
The Mediator subunit MED23 regulates histone 2B mono‐ubiquitylation via RNF20/40 recruitment, leading to transcriptional activation of target genes and illustrating a role for MED23 in myogenesis and tumorigenesis.
The Mediator subunit MED23 is required for H2B mono‐ubiquitination.
The Mediator complex recruits E3 ligase RNF20/40 via MED23.
MED23 links H2B mono‐ubiquitination to transcriptional activation by Mediator.
Mediator and the PAF complex cooperatively stimulate RNF20/40 E3 activity to enhance H2B mono‐ubiquitination.
As an epigenetic regulator, Mediator plays a critical role in cell growth and differentiation.
The EMBO Journal (2015) 34: 2885–2902
- Received February 13, 2015.
- Revision received July 23, 2015.
- Accepted August 10, 2015.
- © 2015 The Authors
- Chromatin signatures at Notch‐regulated enhancers reveal large‐scale changes in H3K56ac upon activation
- Lenka Skalska1,†,
- Robert Stojnic1,2,†,
- Jinghua Li1,†,
- Bettina Fischer2,3,
- Gustavo Cerda‐Moya1,
- Hiroshi Sakai4,
- Shahragim Tajbakhsh4,
- Steven Russell2,3,
- Boris Adryan2,3 and
- Sarah J Bray*,1
- 1Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
- 2Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
- 3Department of Genetics, University of Cambridge, Cambridge, UK
- 4Department of Developmental & Stem Cell Biology, Institut Pasteur, Paris, France
- ↵*Corresponding author. Tel: +44 1223 765222; E‐mail: sjb32{at}cam.ac.uk
↵† These authors contributed equally to this work
Genome‐wide mapping of chromatin changes downstream of Notch signalling defines preferred conditions for Su(H) binding and links rapid changes in H3K56 acetylation to enhancer activation.
Synopsis
Genome‐wide mapping of chromatin changes downstream of Notch signalling defines preferred conditions for Su(H) binding and links rapid changes in H3K56 acetylation to enhancer activation.
Mapping the relationship between chromatin signatures and regions occupied by Su(H) identifies preferred binding contexts.
> 91% of Su(H) motifs are likely masked due to the chromatin environment, while only 7–10% of motifs found in favourable chromatin are bound.
Notch activation triggers rapid changes in acetylation of H3K56 at regulated enhancers.
H3K56ac extends over large regions, requires the histone acetyl‐transferase CBP and precedes changes in transcription.
Rapid changes in H3K56 acetylation are a conserved indicator of enhancer activation.
The EMBO Journal (2015) 34: 1889–1904
- Received September 1, 2014.
- Revision received May 3, 2015.
- Accepted May 13, 2015.
- © 2015 The Authors
- Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2
- Stephen G Dann*,1,
- Michael Ryskin2,
- Anthony M Barsotti2,
- Jonathon Golas2,
- Celine Shi2,
- Miriam Miranda2,
- Christine Hosselet2,
- Luanna Lemon2,
- Judy Lucas2,
- Maha Karnoub3,
- Fang Wang2,
- Jeremy S Myers2,
- Scott J Garza1,
- Maximillian T Follettie2,
- Kenneth G Geles2,
- Anke Klippel3,
- Robert A Rollins2 and
- Valeria R Fantin1
- 1Pfizer Oncology Research Unit, San Diego, CA, USA
- 2Pfizer Oncology Research Unit, Pearl River, NY, USA
- 3Celgene, Summit, NJ, USA
- ↵*Corresponding author. Tel: +1 845 602 2370; Fax: +1 845 602 5557; E‐mail: stephen.dann{at}pfizer.com
The amino acid transporter Lat1 increases cellular S‐adenosylmethionine concentrations and thereby EZH2 activity, and this dictates the differentiation state of cancer cells and tumour growth.
Synopsis
A metabolic–epigenetic feedback loop between the methionine transporter Lat1 and the histone methyltransferase EZH2 dictates differentiation state in a malignant context.
Cells sorted for high CD98/Lat1 expression contain elevated methionine cycle metabolites and more active EZH2 and are more aggressive in lung cancer models.
Amino acid restriction, methionine dropout, or Lat1 shRNA impairs EZH2 activity due to reduction in cellular S‐adenosylmethionine.
Lat1 and EZH2 expressions correlate with a less‐differentiated state as illustrated by spheroid models of cancer cell differentiation, retinoic acid‐mediated transcription, and immunohistochemical analysis of human lung cancer.
EZH2 activity and PRC2 activity derepress Lat1 expression through direct promoter binding and subsequent transcriptional repression of RXRα.
The EMBO Journal (2015) 34: 1773–1785
- Received February 7, 2014.
- Revision received April 10, 2015.
- Accepted April 14, 2015.
- © 2015 The Authors
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