Chromatin, Epigenetics, Genomics & Functional Genomics
- TET‐catalyzed oxidation of intragenic 5‐methylcytosine regulates CTCF‐dependent alternative splicing
- Ryan J Marina1,†,
- David Sturgill1,†,
- Marc A Bailly12†,
- Morgan Thenoz1,†,
- Garima Varma13,
- Maria F Prigge1,
- Kyster K Nanan1,
- Sanjeev Shukla14,
- Nazmul Haque15 and
- Shalini Oberdoerffer*,1
- 1Center for Cancer Research, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD, USA
- 2Merck Research Laboratory, Palo Alto, CA, USA
- 3 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
- 4 Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, India
- 5 National Heart, Lung and Blood Institute, Bethesda, MD, USA
- ↵*Corresponding author. Tel: +1 301 594 8151; Fax: +1 301 496 4951; E‐mail: shalini.oberdoerffer{at}nih.gov
↵† These authors contributed equally to this work
Variations in methylcytosine oxidation state are controlled by the activity of the TET enzymes. TET1/2 activity at intragenic regions allows for enhanced CTCF binding and stimulates the inclusion of alternative exons, thus adding further complexity to the splicing code.
Synopsis
Variations in methylcytosine oxidation state are controlled by the activity of the TET enzymes. TET1/2 activity at intragenic regions allows for enhanced CTCF binding and stimulates the inclusion of alternative exons, thus adding further complexity to the splicing code.
Overlapping methylation at CTCF‐binding sites allows for regulation of alternative pre‐mRNA splicing via variations in TET activity.
The TET proteins directly promote alternative exon inclusion by facilitating CTCF‐associated pol II pausing downstream of weak splice sites.
TET‐catalyzed 5hmC and 5caC are enriched at CTCF‐binding sites in cells and CTCF directly interacts with 5caC‐containing DNA in vitro.
Reduced TET activity results in 5mC‐coupled CTCF eviction and associated exclusion of weak exons from spliced mRNA.
The EMBO Journal (2016) 35: 335–355
- Received October 9, 2015.
- Revision received November 12, 2015.
- Accepted November 25, 2015.
- Published 2015. This article is a U.S. Government work and is in the public domain in the USA
- A hit‐and‐run heat shock factor governs sustained histone methylation and transcriptional stress memory
- 1Institute for Biochemistry and Biology, University of Potsdam, Potsdam, Germany
- 2Institute of Biology, Free University Berlin, Berlin, Germany
- ↵*Corresponding author. Tel: +49 331 9772647; E‐mail: isabel.baeurle{at}uni-potsdam.de
Stress exposure can prime for an enhanced response upon re‐exposure. In Arabidopsis, heat stress‐mediated priming is associated with stable histone H3 lysine 4 di‐ and trimethylation and requires transcription factor HSFA2 that only transiently binds to the primed gene loci.
Synopsis
Stress exposure can prime for an enhanced response upon re‐exposure. In Arabidopsis, heat stress‐mediated priming is associated with stable histone H3 lysine 4 di‐ and trimethylation and requires transcription factor HSFA2 that only transiently binds to the primed gene loci.
Heat stress primes genes for sustained activation and/or enhanced induction upon recurring stress.
This transcriptional memory is linked to induction of histone H3 lysine 4 di‐ and trimethylation.
Transcription factor HSFA2 is required for transcriptional memory.
HSFA2 only transiently associates with the gene loci, suggesting it acts in a hit‐and‐run mode.
The EMBO Journal (2016) 35: 162–175
- Received July 17, 2015.
- Revision received November 9, 2015.
- Accepted November 13, 2015.
- © 2015 The Authors
- 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
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