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| Open AccessPlatelet function is modified by common sequence variation in megakaryocyte super enhancers
Numerous genetic variants, including those located in the non-coding regions of the genome, are known to be associated with blood cells traits. Here, Frontini and colleagues investigate their potential regulatory functions using epigenomic data and promoter long-range interactions.
- Romina Petersen
- , John J. Lambourne
- & Mattia Frontini
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| Open AccessTargeted DNA methylation in vivo using an engineered dCas9-MQ1 fusion protein
Understanding how DNA methylation regulates gene expression requires the capacity to deploy it to regions of interest. The authors generate a highly rapid and locus-specific CpG methylation tool by fusing dCas9 to MQ1 DNA methyltransferase and show efficacy at multiple sitesin vitro and in vivo.
- Yong Lei
- , Xiaotian Zhang
- & Margaret A. Goodell
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| Open AccessTen-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis
Epigenetic modifications, such as DNA methylation, play an important role in adult neurogenesis. Here the authors show that Tet2, which converts 5mC to 5hmC, interacts with the transcription factor Foxo3a and regulates critical genes related to the proliferation and differentiation of adult neural stem cells.
- Xuekun Li
- , Bing Yao
- & Peng Jin
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Article
| Open AccessFlipping between Polycomb repressed and active transcriptional states introduces noise in gene expression
Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.
- Gozde Kar
- , Jong Kyoung Kim
- & Sarah A. Teichmann
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Article
| Open AccessDOT1L safeguards cartilage homeostasis and protects against osteoarthritis
DOT1L is one of the few genes linked to osteoarthritis by human GWAS. Here the authors show that DOT1L-dependent histone methylation protects homeostasis of articular chondrocytes by SIRT1-dependent inhibition of canonical WNT signalling, and that inhibition of DOT1L can drive osteoarthritic disease in mice.
- Silvia Monteagudo
- , Frederique M. F. Cornelis
- & Rik J. Lories
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Article
| Open AccessDrug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour
Drug addiction is partially heritable but the non-genetic inheritance mechanisms are not well understood. The authors show that motivation of male rats in response to cocaine self-administration elicit susceptibility and/or decreased resistance to developing addiction like behaviour in offspring.
- Qiumin Le
- , Biao Yan
- & Lan Ma
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Article
| Open AccessA promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers
Promoter-proximal transcripts have been proposed to act ascis-acting elements regulating transcription. Here, the authors provide evidence that a promoter-proximal RNA, in combination with other epigenetic regulators, controls transcription of E-cadherin in epithelial cancers.
- Giuseppina Pisignano
- , Sara Napoli
- & Carlo V. Catapano
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Article
| Open AccessTailing and degradation of Argonaute-bound small RNAs protect the genome from uncontrolled RNAi
While RNA interference is a highly conserved mechanism of gene regulation, how Argonaute-bound small RNAs are targeted for degradation is not well understood. Here the authors show that Cid14 and Cid16 target Argonaute-bound small RNAs for degradation and protect the genome from uncontrolled RNAi activity.
- Paola Pisacane
- & Mario Halic
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Article
| Open AccessDesign of synthetic epigenetic circuits featuring memory effects and reversible switching based on DNA methylation
Recording systems would allow synthetic organisms to store a ‘memory’ of a past event for future reference. Here the authors design an epigenetic memory system inE. colithat methylates DNA in response to exogenous and endogenous signals.
- Johannes A. H. Maier
- , Raphael Möhrle
- & Albert Jeltsch
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Article
| Open AccessSelective BET bromodomain inhibition as an antifungal therapeutic strategy
BET proteins bind chromatin through their bromodomains (BDs) to regulate transcription and chromatin remodelling. Here, the authors show that the BET protein Bdf1 is essential for the fungal pathogenCandida albicans, and report compounds that inhibit the Bdf1 BDs with high selectivity over human BDs.
- Flore Mietton
- , Elena Ferri
- & Carlo Petosa
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Article
| Open AccessGenetic architecture of epigenetic and neuronal ageing rates in human brain regions
Studies on the ‘epigenetic clock’, a recently identified ageing biomarker, suggest that pathology might be linked to tissue-specific accelerated ageing. Here, the authors investigate ageing in the human brain and identify genetic loci associated with accelerated ageing in different brain regions.
- Ake T. Lu
- , Eilis Hannon
- & Steve Horvath
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Article
| Open AccessLocus-specific histone deacetylation using a synthetic CRISPR-Cas9-based HDAC
CRISPR-Cas9 has been utilized, through the fusion of catalytic dead nuclease with chromatin-remodellers, to modify the epigenetic state of specific loci. Here the authors manipulate locus-specific histone acetylation and describe the parameters that need to be considered for its use.
- Deborah Y. Kwon
- , Ying-Tao Zhao
- & Zhaolan Zhou
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Article
| Open AccessIntron retention is regulated by altered MeCP2-mediated splicing factor recruitment
Intron retention is a conserved mechanism that controls gene expression but its regulation is poorly understood. Here, the authors provide evidence that DNA methylation regulates intron retention and find reduced MeCP2 occupancy and splicing factor recruitment near affected splice junctions.
- Justin J. -L. Wong
- , Dadi Gao
- & John E. J. Rasko
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Article
| Open AccessArabidopsis proteins with a transposon-related domain act in gene silencing
Host genomes have evolved multiple silencing mechanisms to repress transposable element activity. Here Ikedaet al. show that the Arabidopsis MAIL1 and MAINgenes encode a retrotransposon-related plant mobile domain and define an alternative silencing pathway largely independent of DNA methylation and siRNAs.
- Yoko Ikeda
- , Thierry Pélissier
- & Olivier Mathieu
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Article
| Open AccessTet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells
TET2 catalyses DNA demethylation and is mutated in various blood cancers; in particularTet2null mice develop haematological neoplasms. Here the authors show that this effect could be due to the increased frequency of mutation associated with TET2 loss in haematopoietic stem/progenitor cells.
- Feng Pan
- , Thomas S. Wingo
- & Mingjiang Xu
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Article
| Open AccessThe histone H3K9 methyltransferase SUV39H links SIRT1 repression to myocardial infarction
The molecular pathways regulating the cardioprotective activity of deacetylase sirtuin-1 are unknown. Here, Yanget al. show that histone H3K9 methyltransferase SUV39H and HP1gamma cooperatively methylate H3K9 on the sirtuin-1 promoter and inhibit sirtuin-1 transcription, and show that inhibition of SUV39H in mice is cardioprotective.
- Guang Yang
- , Xinyu Weng
- & Aijun Sun
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Article
| Open AccessEpigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions
Arthritis affects different joints variably despite systemic inflammatory cues. Here the authors show anatomical differences in the transcriptome, epigenome and function of synovial fibroblasts that might affect susceptibility to site-specific joint diseases.
- Mojca Frank-Bertoncelj
- , Michelle Trenkmann
- & Caroline Ospelt
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Article
| Open AccessA natural tandem array alleviates epigenetic repression of IPA1 and leads to superior yielding rice
Breeding of rice with ideal plant architecture has increased rice yield worldwide. Here Zhanget al. show that, in the super rice variety YY12, this ideal plant architecture trait arose from three distal tandem repeats that are associated with an open chromatin state and increased expression of the IPA1gene.
- Lin Zhang
- , Hong Yu
- & Jiayang Li
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Article
| Open AccessThe SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers
SWI/SNF chromatin remodelling complex is a major regulator of chromatin structure and of transcription. Here, using mouse embryonic fibroblasts and human rhabdoid tumour cells, the authors provide evidence that SWI/SNF functions as a regulator of enhancers.
- Burak H. Alver
- , Kimberly H. Kim
- & Charles W. M. Roberts
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| Open AccessThe non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression
Functional characterisation of non-coding risk variants for colorectal cancer is missing. Here the authors conduct a large-scale proteome-wide analysis of disease associated SNPs to characterize allele-specific transcription factor binding landscape in colorectal cancer and identify one functionally significant SNP.
- Ning Qing Liu
- , Menno ter Huurne
- & Hendrik G. Stunnenberg
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| Open AccessHOPX hypermethylation promotes metastasis via activating SNAIL transcription in nasopharyngeal carcinoma
HOPX is a transcription factor epigenetically silenced in several cancers. Here the authors, by analysing methylation profiles, identify HOPX as a suppressor of metastasis in nasopharyngeal carcinoma: mechanistically HOPX inhibitsSNAILtranscription through deacetylation-mediated silencing.
- Xianyue Ren
- , Xiaojing Yang
- & Jun Ma
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Article
| Open AccessRepo-Man/PP1 regulates heterochromatin formation in interphase
Repo-Man is a chromosome-binding subunit of protein phosphatase 1 to regulate mitosis. Here, de Castro and colleagues show that Repo-Man also regulates heterochromatin during interphase, and regulates gene repression and chromatin organization.
- Inês J. de Castro
- , James Budzak
- & Paola Vagnarelli
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Article
| Open AccessPraja1 E3 ubiquitin ligase promotes skeletal myogenesis through degradation of EZH2 upon p38α activation
In skeletal muscle progenitors, EZH2 maintains myogenic genes in a repressed state, but during differentiation its levels are reduced via unknown mechanisms. Here the authors show that during myogenesis, p38α kinase phosphorylates EZH2 and targets it for degradation by the ubiquitin ligase PRAJA1.
- Silvia Consalvi
- , Arianna Brancaccio
- & Daniela Palacios
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Article
| Open AccessEnvironmental stresses induce transgenerationally inheritable survival advantages via germline-to-soma communication in Caenorhabditis elegans
Environmental stress causes epigenetic changes but it is unclear if such changes are transgenerational. Here, the authors show that inC. elegans, increased resistance to oxidative stress and proteotoxicity in the parental generation and linked epigenetic changes are transmitted to subsequent generations.
- Saya Kishimoto
- , Masaharu Uno
- & Eisuke Nishida
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Article
| Open AccessExport of piRNA precursors by EJC triggers assembly of cytoplasmic Yb-body in Drosophila
In Drosophila ovarian follicle cells, piRNAs generated from RNA precursors are processed in cytoplasmic Yb-bodies. The authors identify the exportin and the exon junction complexes as required to transfer precursors to cytoplasm. They also show that Yb-body formation requires piRNA precursor export.
- Cynthia Dennis
- , Emilie Brasset
- & Chantal Vaury
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Article
| Open AccessUVR2 ensures transgenerational genome stability under simulated natural UV-B in Arabidopsis t haliana
As sessile organisms, plants are exposed to recurrent solar UV-B radiation that can induce DNA damage. Here, the authors characterize mutations that occur in Arabidopsisunder light regimes simulating natural UV-B exposure and find that the UVR2 photolyase is the major component required to maintain genome stability.
- Eva-Maria Willing
- , Thomas Piofczyk
- & Ales Pecinka
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| Open AccessJarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2
The Polycomb repressive complexes PRC1 and PRC2 play a central role in developmental regulation of the genome in multicellular organisms. Here the authors describe how the PRC2 cofactor Jarid2 mediates the recruitment of the PRC2 complex to chromatin via interaction with H2AK119u1.
- Sarah Cooper
- , Anne Grijzenhout
- & Neil Brockdorff
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Article
| Open AccessIntegrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease
Epigenetic perturbations may be an important factor in diseases where both genes and environment play a role. Here, Ventham and colleagues show that DNA methylation changes in inflammatory bowel disease are related to the underlying genotype, and are associated with cell-specific changes to gene expression.
- N. T. Ventham
- , N. A. Kennedy
- & J. Satsangi
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Article
| Open AccessEpigenetic and genetic components of height regulation
Adult height has a strong genetic component and is highly heritable. Here the authors whole-genome sequence 8,453 Icelanders and find novel parent-of-origin derived associations in IGF2-H19 and DLK1-MEG3.
- Stefania Benonisdottir
- , Asmundur Oddsson
- & Kari Stefansson
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| Open AccessEpigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance
Centromeres are centrochromatin domains with CENP-A and H3 nucleosomes carrying transcription-associated modifications. Here the authors target synthetic modules to the centromeres to show that transcription plus histone modifications are required for CENP-A assembly and centrochromatin maintenance.
- Oscar Molina
- , Giulia Vargiu
- & William C. Earnshaw
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Article
| Open AccessDNA looping mediates nucleosome transfer
Replicating the genome presents a major challenge to the maintenance of the epigenetic landscape. Here the authors use a minimal experimental system to show how nucleosomes are transferred to double-stranded DNA, with the transfer mediated by a quantitative loop formation model.
- Lucy D. Brennan
- , Robert A. Forties
- & Michelle D. Wang
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Article
| Open AccessGenetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer
Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation ofMYC.
- Steffen Grampp
- , James L. Platt
- & Johannes Schödel
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Article
| Open AccessMutually exclusive sense–antisense transcription at FLC facilitates environmentally induced gene repression
Antisense transcription from genic regions is a common phenomenon. Here Rosa et al. use single molecule FISH to show that during vernalization in Arabidopsis, cold-induced antisense transcription of COOLAIR is mutually exclusive to sense-strand transcription of the flowering regulator FLCfrom the same loci.
- Stefanie Rosa
- , Susan Duncan
- & Caroline Dean
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Article
| Open AccessAbundant DNA 6mA methylation during early embryogenesis of zebrafish and pig
DNA 6mA is a poorly understood epigenetic mark present at a low abundance in eukaryotic genomes. Here the authors observe high levels in zebrafish and pig during early embryogenesis enriched to repetitive regions of the genome and followed by attenuation during development.
- Jianzhao Liu
- , Yuanxiang Zhu
- & Chuan He
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Article
| Open AccessHistone variant H3F3A promotes lung cancer cell migration through intronic regulation
Histone variants act as transcriptional activators and repressors and have been linked to cancer progression. Park and Choi et al. show that the histone H3.3 overexpression is associated with early-stage lung cancer, and promotes cancer cell migration by upregulating a G-protein-coupled receptor.
- Seong-Min Park
- , Eun-Young Choi
- & In-Hoo Kim
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Article
| Open AccessAntagonistic roles of Drosophila Tctp and Brahma in chromatin remodelling and stabilizing repeated sequences
Genome stability is important for normal cellular function. Here, Hong and Choi show that translationally controlled tumour protein (TCTP) in Drosophilaregulates pericentromeric chromatin remodelling and transcription via negatively regulating a chromatin remodeler Brahma.
- Sung-Tae Hong
- & Kwang-Wook Choi
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Article
| Open AccessEpigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity
Gene expression is regulated by enhancers and super-enhancers, which can be identified by chromatin profiling. Here, the authors surveyed gastric cancer samples and cell lines to identify enhancer elements exhibiting somatic alterations.
- Wen Fong Ooi
- , Manjie Xing
- & Patrick Tan
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Article
| Open AccessMice produced by mitotic reprogramming of sperm injected into haploid parthenogenotes
It is unclear what regulates gamete reprogramming competence. Here, the authors inject sperm into parthenogenetic embryos, generating viable offspring and show that mouse embryos in the mitotic cell cycle can reprogram sperm for full term development.
- Toru Suzuki
- , Maki Asami
- & Anthony C. F. Perry
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Article
| Open AccessFunctional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus
A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.
- Kate Lawrenson
- , Siddhartha Kar
- & Simon A. Gayther
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Article
| Open AccessType II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations
Enteropathy associated T-cell lymphoma -EATL- affects the intestine and there are two different subtypes. In this study, the authors carry out exome sequencing of the type II variant and find that it is characterized by recurrent mutations in the histone methyltransferase SETD2 that are accompanied by altered H3K6 methylation.
- Annalisa Roberti
- , Maria Pamela Dobay
- & Laurence de Leval
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Article
| Open AccessDissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals
There is crosstalk between the maintenance of DNA methylation and histone methylation. Here, the authors create an Uhrf1 knockin mouse model that abolishes the H3K9me2/3-binding activity of Uhrf1, and show that DNA maintenance methylation in mammals is largely independent of H3K9 methylation.
- Qian Zhao
- , Jiqin Zhang
- & Jiemin Wong
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Article
| Open AccessEarly programming of the oocyte epigenome temporally controls late prophase I transcription and chromatin remodelling
Meiotically arrested oocytes retain transcriptional ability despite chromosome condensation. Here, the authors show that Drosophilaoocytes regulate meiotic transcription and chromatin remodelling through the programming, in early oogenesis, of an extremely diversified epigenome.
- Paulo Navarro-Costa
- , Alicia McCarthy
- & Rui G. Martinho
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Article
| Open AccessDNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy
5-hydroxymethylation of cysteine (5-hmC) plays a role in epigenetic regulation. Here the authors analyse the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes and show that the dynamic modulation of hydroxymethylated DNA is important for cardiomyocyte gene expression programming in heart development and failure.
- Carolina M. Greco
- , Paolo Kunderfranco
- & Gianluigi Condorelli
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Article
| Open AccessExtra-coding RNAs regulate neuronal DNA methylation dynamics
DNA methylation in the brain is a dynamic process, but gene-specific regulation of this process is poorly understood. Here, Day and colleagues show that extra-coding RNAs interact with DNA methyltransferases and regulate neuronal DNA methylation to control gene expression in locus-specific manner in neurons.
- Katherine E. Savell
- , Nancy V. N. Gallus
- & Jeremy J. Day
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Article
| Open AccessHypoxia causes transgenerational impairments in reproduction of fish
Hypoxia has diverse effects on aquatic life. Wang et al.show that reproductive defects resulting from hypoxia are epigenetically heritable in Japanese rice fish, and that this intergenerational inheritance is accompanied by differential methylation and gene expression in sperm.
- Simon Yuan Wang
- , Karen Lau
- & Rudolf Shiu-Sun Wu
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Article
| Open AccessAcetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia
Cancer cells under stress use acetate to maintain the acetyl-CoA pool and fuel lipid biosynthesis. Here, the authors show that acetate also promotes de novo lipid synthesis by increasing histone acetylation at the promoters of lipogenic enzymes ACACA and FASN, thus inducing their expression.
- Xue Gao
- , Shu-Hai Lin
- & Qun-Ying Lei
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Article
| Open AccessStructural basis for the recognition of guide RNA and target DNA heteroduplex by Argonaute
Argonaute proteins are important in the silencing machinery with some regulatory RNAs. Here, the authors solve the structure of an argonaute protein in complex with both the guide RNA and target DNA and propose a mechanism for their recognition.
- Tomohiro Miyoshi
- , Kosuke Ito
- & Toshio Uchiumi
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Article
| Open AccessMTHFD1 controls DNA methylation in Arabidopsis
DNA methylation contributes to transcriptional silencing. Here, Groth et al.show that mutant plants defective in MTHFD1, an enzyme involved in folate metabolism, have a DNA hypomethylation phenotype highlighting the link between one-carbon metabolism and DNA methylation, which is mediated by SAM as a common methyl donor.
- Martin Groth
- , Guillaume Moissiard
- & Steven E. Jacobsen
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Article
| Open AccessJoint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes
Rheumatoid arthritis is an inflammatory disease that selectively affects different joints. Here the authors show that gene expression and DNA methylation patterns of fibroblast-like synoviocytes differ between hip and knee joints in patients with RA, thus providing epigenetic and transcriptomic evidence for this anatomic selectivity of inflammation.
- Rizi Ai
- , Deepa Hammaker
- & Wei Wang