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| Open AccessCaspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis
Caspases are most closely associated with cell death, but many have other cellular functions. Here, Das et al. find that upon metabolic stress, caspase-10 cleaves ACLY to regulate metabolic homeostasis and epigenetic reprogramming by altering Acetyl-CoA levels.
- Rajni Kumari
- , Ruhi S. Deshmukh
- & Sanjeev Das
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Article
| Open AccessMLL1 is required for PAX7 expression and satellite cell self-renewal in mice
PAX7 transcription factor specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. Here authors find that Mll1 deletion in myoblasts in mice results in reduced H3K4me3 at both Pax7 and Myf5 promoters, reduced Pax7 and Myf5 expression, and proliferation defects.
- Gregory C. Addicks
- , Caroline E. Brun
- & Michael A. Rudnicki
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Article
| Open AccessDynamic changes of muscle insulin sensitivity after metabolic surgery
Surgical weight-loss interventions improve insulin sensitivity via incompletely understood mechanisms. Here the authors assess skeletal muscle epigenetic changes in individuals with obesity following metabolic surgery and compare them with data from individuals without obesity.
- Sofiya Gancheva
- , Meriem Ouni
- & Michael Roden
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Article
| Open AccessCryoEM structures of Arabidopsis DDR complexes involved in RNA-directed DNA methylation
RNA polymerase V transcription in plants, which is needed DNA methylation and transcriptional silencing, requires components of the DDR complex. Here the authors show that all components of the DDR complex co-localize with Pol V and report the cryoEM structures of two complexes associated with Pol V recruitment.
- Somsakul Pop Wongpalee
- , Shiheng Liu
- & Steven E. Jacobsen
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Article
| Open AccessAssisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood
Use of Assisted Reproductive Technologies (ART) is increasing globally but their impact on long term health remains unclear. Here the authors show that ART-conceived individuals show variation in epigenetic profile at birth that largely resolves by adulthood, with no evidence of an impact on long term outcomes.
- Boris Novakovic
- , Sharon Lewis
- & Richard Saffery
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Article
| Open AccessA phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease of substantial phenotypic heterogeneity in different ethnic groups. Here, using data from a multi-ethnic cohort, the authors describe an approach based on clinical and molecular data to subtype SLE patients into three clusters of severity.
- Cristina M. Lanata
- , Ishan Paranjpe
- & Lindsey A. Criswell
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Article
| Open AccessMapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq)
The authors introduce ACT-seq: a Tn5-based method for rapidly profiling epigenetic marks in bulk-cell and single-cell samples. ACT-seq avoids many laborious or time-consuming steps required for similar techniques including chromatin fragmentation and end repair.
- Benjamin Carter
- , Wai Lim Ku
- & Keji Zhao
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Article
| Open AccessPAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma
Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.
- Melusine Bleu
- , Swann Gaulis
- & Giorgio G. Galli
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Article
| Open AccessFunctional genetic variants can mediate their regulatory effects through alteration of transcription factor binding
Functional variants have been proposed to alter transcription factor binding. Here, the authors provide direct evidence that functional variants within the TBC1D4 gene, encoding an NFκB binding site, can alter transcription factor binding, and use CRISPR-Cas9 to reveal localization of the transcription factor to be the regulator of chromatin accessibility and p65 binding and ultimately TBC1D4 expression.
- Andrew D. Johnston
- , Claudia A. Simões-Pires
- & John M. Greally
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Article
| Open AccessPhc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression
Mobilization of hematopoietic stem and progenitor cells (HSPCs) into the circulation is essential for maintaining homeostasis. Here, the authors show that Phc2 in bone marrow stromal cells represses the cell adhesion molecule Vcam1 and facilitates mobilization of HSPCs through regulation of epigenetic marks.
- Joonbeom Bae
- , Sang-Pil Choi
- & Taehoon Chun
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Article
| Open AccessTransposition favors the generation of large effect mutations that may facilitate rapid adaption
The contribution of transposable elements (TEs) to the creation of heritable mutations is unknown. Here the authors show in Arabidopsis that TEs accumulate exponentially once mobilized and that COPIA retrotransposons preferentially integrate in environmental response genes in a H2A.Z-dependent manner.
- Leandro Quadrana
- , Mathilde Etcheverry
- & Vincent Colot
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Article
| Open AccessMAPCap allows high-resolution detection and differential expression analysis of transcription start sites
The position, shape and number of transcription start sites (TSS) regulate gene expression. Here authors present MAPCap, a method for high-resolution detection and differential expression analysis of TSS, and apply MAPCap to early fly development, detecting stage and sex-specific promoter and enhancer activity.
- Vivek Bhardwaj
- , Giuseppe Semplicio
- & Asifa Akhtar
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| Open AccessArabidopsis SWR1-associated protein methyl-CpG-binding domain 9 is required for histone H2A.Z deposition
The SWI2/SNF2-Related 1 chromatin remodeling complex (SWR1-C) is important for gene regulation, but its composition remains largely uncharacterized in plants. Here, the authors report that methyl-CpG-binding domain 9 (MBD9) is a SWR1-C interacting protein required for histone H2A.Z deposition in Arabidopsis.
- Magdalena E. Potok
- , Yafei Wang
- & Steven E. Jacobsen
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Article
| Open AccessThe histone methyltransferase Setd2 is indispensable for V(D)J recombination
The repertoire of adaptive immune receptor is generated by V(D)J recombination, somatic rearrangements of V, D and J gene segments, in the respective loci. Here the authors show that the deficiency of Setd2, a histone methyl transfer, impairs V(D)J recombination and induces severe developmental blocks in both T and B lineages.
- Zhongzhong Ji
- , Yaru Sheng
- & Helen He Zhu
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Article
| Open AccessMethylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases
Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.
- W. K. Jacky Lam
- , Peiyong Jiang
- & Y. M. Dennis Lo
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Article
| Open AccessSystematic allelic analysis defines the interplay of key pathways in X chromosome inactivation
Xist RNA is the master regulator of X chromosome inactivation. Here the authors describe a systematic analysis of Xist-mediated allelic silencing in mouse ESC models and define the contribution of different pathways that regulate gene silencing.
- Tatyana B. Nesterova
- , Guifeng Wei
- & Neil Brockdorff
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Article
| Open AccessZebrafish preserve global germline DNA methylation while sex-linked rDNA is amplified and demethylated during feminisation
Germline cells transfer genetic information to offspring, and in zebrafish, drive sex determination. Here the authors report that, unlike mammals, the germline of zebrafish does not undergo genome-wide DNA methylation erasure, while amplifying and demethylating sex-linked rDNA during feminisation.
- Oscar Ortega-Recalde
- , Robert C. Day
- & Timothy A. Hore
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Article
| Open AccessDetection of cell-type-specific risk-CpG sites in epigenome-wide association studies
Cellular heterogeneity is one of the major confounding factors in EWAS studies. Here the authors present a statistical method, HIgh REsolution (HIRE), which enables the detection of risk-CpG sites for individual cell types.
- Xiangyu Luo
- , Can Yang
- & Yingying Wei
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Article
| Open AccessThe nasal methylome as a biomarker of asthma and airway inflammation in children
Epigenetic differences in nasal epithelium have been proposed as a biomarker for lower airway disease and asthma. Here, in epigenome-wide association studies for asthma and other airway traits using nasal swabs, the authors identify differentially methylated CpGs that highlight genes involved in TH2 response.
- Andres Cardenas
- , Joanne E. Sordillo
- & Diane R. Gold
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| Open AccessRetention of paternal DNA methylome in the developing zebrafish germline
Germ cells are the means of transferring genetic information to the next generation. Here the authors characterise the DNA methylomes of zebrafish primordial germ cells and find that, unlike mammals, the zebrafish germ cells do not undergo genome-wide DNA demethylation but rather retain paternal DNA methylation patterns
- Ksenia Skvortsova
- , Katsiaryna Tarbashevich
- & Ozren Bogdanovic
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Article
| Open AccessMonoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex
Monoallelic expression of variant surface glycoprotein genes (VSGs) is essential for immune evasion by Trypanosoma brucei. Here, Faria et al. show that the VEX protein complex controls VSG allelic exclusion, and that CAF‐1 sustains inheritance of the VEX‐complex in association with the active VSG.
- Joana Faria
- , Lucy Glover
- & David Horn
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Article
| Open AccessThe effect of X-linked dosage compensation on complex trait variation
Dosage compensation (DC) on the X chromosome has predictable effects on genetic and phenotypic trait variance. Here, the authors use information for 20 quantitative traits in the UK Biobank and across-tissue gene expression to compare X-linked heritability and the effects of trait-associated SNPs between the sexes.
- Julia Sidorenko
- , Irfahan Kassam
- & Peter M. Visscher
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Article
| Open AccessThe transcription factor OsSUF4 interacts with SDG725 in promoting H3K36me3 establishment
The distribution of H3K36me3 varies between species. Here Liu et al. show that the OsSUF4 transcription factor binds its target motif via a zinc finger domain to promote H3K36 methyltransferase targeting close to the transcription start site of genes including the flowering regulators RFT1 and Hd3a.
- Bing Liu
- , Yuhao Liu
- & Aiwu Dong
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Article
| Open AccessPRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments
The inactive X (Xi)-specific S1/S2 chromosome compartments are merged by SMCHD1, but how the S1/S2 structure is constructed is unclear. The authors find that PRC1 drives the formation of S1/S2s and that the stepwise folding process of the Xi facilitates Xist RNA spreading between Xi compartments.
- Chen-Yu Wang
- , David Colognori
- & Jeannie T. Lee
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Article
| Open AccessTargeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia
There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.
- Charles C. Bell
- , Katie A. Fennell
- & Mark A. Dawson
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Article
| Open AccessThe Polycomb protein Ezl1 mediates H3K9 and H3K27 methylation to repress transposable elements in Paramecium
H3K9me3 and H3K27me3 chromatin silencing marks are usually deposited by different SET-domain proteins. Here the authors show that the Enhancer-of-zeste-like protein Ezl1, from the unicellular eukaryote Paramecium tetraurelia, catalyzes methylation of histone H3 in vitro and in vivo with an apparent specificity toward K9 and K27, and controls the repression of transposable elements.
- Andrea Frapporti
- , Caridad Miró Pina
- & Sandra Duharcourt
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Article
| Open AccessAn integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
Our understanding of the functional link between differential DNA methylation and type 2 diabetes and obesity remains limited. Here the authors present a blood-based EWAS of fasting glucose and insulin among 4808 non-diabetic Europeans and identify nine CpGs not previously implicated in glucose, insulin homeostasis and diabetes.
- Jun Liu
- , Elena Carnero-Montoro
- & Cornelia M. van Duijn
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| Open AccessIntegrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.
- Darina Czamara
- , Gökçen Eraslan
- & Elisabeth B. Binder
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Article
| Open AccessH3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans
Substitution of lysine 27 with methionine in histone H3.3 (H3.3K27M) is a driver mutation of pediatric high-grade gliomas. Here the authors show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans, through JNK pathway misregulation.
- Kamila Delaney
- , Maude Strobino
- & Florian A. Steiner
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Article
| Open AccessKidney cytosine methylation changes improve renal function decline estimation in patients with diabetic kidney disease
Patients with diabetes commonly develop diabetic kidney disease (DKD). Here Gluck et al. identify a set of probes differentially methylated in renal samples from patients with DKD, and find that inclusion of these methylation probes improves current prediction models of renal function decline.
- Caroline Gluck
- , Chengxiang Qiu
- & Katalin Susztak
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Article
| Open AccessDetection of DNA base modifications by deep recurrent neural network on Oxford Nanopore sequencing data
DNA modification generates unique electric signals in Oxford Nanopore sequencing data but the signals can be complicated to decipher. Here, the authors develop a deep learning framework, DeepMod, to detect DNA base modifications including 5mC and 6mA using Nanopore sequencing data
- Qian Liu
- , Li Fang
- & Kai Wang
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Article
| Open AccessInterspecies conservation of organisation and function between nonhomologous regional centromeres
Although the centromere-specific histone CENP-A usually assembles on specific genomic sequences, centromeric DNA is not conserved. Here the authors characterize the genome and centromeres of related fission yeasts and provide evidence that Schizosaccharomyces centromere DNA possesses intrinsic conserved properties that promote assembly of CENP-A chromatin.
- Pin Tong
- , Alison L. Pidoux
- & Robin C. Allshire
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Article
| Open AccessEpigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms
Epigenetic control of enhancers may contribute to neurological disease. Here the authors carry out genome-wide analysis of DNA methylation in neurons isolated postmortem from patients with Alzheimer’s disease.
- Peipei Li
- , Lee Marshall
- & Viviane Labrie
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Article
| Open Access6mA-DNA-binding factor Jumu controls maternal-to-zygotic transition upstream of Zelda
N6-methyladenine (6mA) DNA modification is a dynamic epigenetic mark in Drosophila embryos, but how 6mA is decoded is unclear. Here, the authors show that the protein Jumu binds 6mA-marked DNA to regulate the maternal-to-zygotic transition, partly through regulation the expression of the 6mA marked pioneer factor zelda.
- Shunmin He
- , Guoqiang Zhang
- & Dahua Chen
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Article
| Open AccessPFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism
PFA tumours express high levels of EZHIP (also known as CXORF67). Here the authors find that EZHIP directly interacts with the active site of EZH2 and is a competitive inhibitor of PRC2 and that EZHIP gives rise to H3K27me3 genomic profile similar to the K27M oncohistone.
- Siddhant U. Jain
- , Truman J. Do
- & Peter W. Lewis
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Article
| Open AccessTargeted removal of epigenetic barriers during transcriptional reprogramming
Master transcription factors dominantly direct cell fate and barriers ensuring their tissue specific silencing are not clearly defined. Here, the authors demonstrate that inefficient targeted transactivation of Sox1 in neural progenitor cells is surmountable through targeted promoter demethylation using dCas9-Tet1.
- Valentin Baumann
- , Maximilian Wiesbeck
- & Stefan H. Stricker
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Article
| Open AccessSREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer
ERα breast cancer can relapse to metastatic disease following endocrine therapy. Here, the authors find that when aromatase inhibitor treatment resistance develops, epigenomic reprogramming drives Keratin-80 upregulation via SREBP1, and promotes cytoskeletal rearrangements that drive cancer cell invasion.
- Ylenia Perone
- , Aaron J. Farrugia
- & Luca Magnani
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Article
| Open AccessDNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis
Monozygotic (MZ) twins are ideal to study the influence of non-genetic factors on complex phenotypes. Here, Souren et al. perform an EWAS in peripheral blood mononuclear cells from 45 MZ twins discordant for multiple sclerosis and identify disease and treatment-associated epigenetic markers.
- Nicole Y. Souren
- , Lisa A. Gerdes
- & Jörn Walter
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Article
| Open AccessDNA methylation repels targeting of Arabidopsis REF6
REF6 is a H3K27me3 histone demethylase that targets regions of active chromatin in the Arabidopsis genome. Here Qiu et al. show that REF6 preferentially binds unmethylated DNA via its zinc-finger domains suggesting that DNA methylation might deter REF6 binding in heterochromatin.
- Qi Qiu
- , Hailiang Mei
- & Xiaofeng Cao
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Article
| Open AccessCanonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing
Polycomb Repressive Complexes PRC1 and PRC2 catalyse distinct chromatin modifications to promote gene silencing. Here the authors use reversible tethering of Polycomb proteins to ectopic sites in mouse ESCs and find that canonical but not variant PRC1 can trigger sequence-independent propagation of Polycomb-mediated transcriptional repression.
- Hagar F. Moussa
- , Daniel Bsteh
- & Oliver Bell
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Article
| Open AccessMeta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
Birthweight has been found to associate with later-life health outcomes. Here the authors perform a meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, identifying differentially methylated CpGs in neonatal blood that associate with birthweight.
- Leanne K. Küpers
- , Claire Monnereau
- & Janine F. Felix
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Article
| Open AccessBRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors
Mutations of the SWI/SNF chromatin-remodeling complex member SMARCB1 can cause malignant rhaboid tumors. Here the authors report a BRD9-containing SWI/SNF subcomplex that lacks SMARCB1 and its requirement for the survival of rhaboid tumors.
- Xiaofeng Wang
- , Su Wang
- & Charles W. M. Roberts
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Article
| Open AccessThe H2A.Z histone variant integrates Wnt signaling in intestinal epithelial homeostasis
The histone variant, H2A.Z is known to regulate gene expression and cell proliferation. Here the authors show that H2A.Z has a central role in the control of intestinal epithelial homeostasis in mice, by preventing terminal differentiation of intestinal progenitors.
- Jérémie Rispal
- , Lucie Baron
- & Fabrice Escaffit
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Article
| Open AccessA DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice
PWWP domains of DNMT3A and DNMT3B are proposed to interact with H3K36me3. Here the authors present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain and find this causes dominant postnatal growth retardation, with aberrant progressive gain of DNA methylation across domains marked by H3K27me3 in adult tissues.
- Gintarė Sendžikaitė
- , Courtney W. Hanna
- & Gavin Kelsey
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Article
| Open AccessPartially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
In cancer, global DNA methylation loss and CpG island hypermethylation are commonly observed. Here, in breast cancer the authors find that hyper-variability of partially methylated domains is the prime source of DNA methylation variation and that these domains fuel CpG island hypermethylation.
- Arie B. Brinkman
- , Serena Nik-Zainal
- & Hendrik G. Stunnenberg
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Article
| Open AccessTET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn
The potential role of TET proteins in adult neurogenesis is unknown. In this study, authors show that TET3 is essentially required for the maintenance of the NSC pool in the adult subventricular zone niche by preventing premature differentiation of NSCs, via direct binding and repression of the paternal transcribed allele of the imprinted gene Snrpn
- Raquel Montalbán-Loro
- , Anna Lozano-Ureña
- & Sacri R. Ferrón
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Article
| Open AccessDissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity
Polycomb repressive complexes PRC1 and PRC2 act non-redundantly at target genes to regulate transcription. Here the authors present engineered mouse ESCs targeting the PRC2 subunits EZH1 and EZH2 to discriminate between contributions of distinct H3K27 methylation states and the presence of PRC2/1 at chromatin, and provide evidence for the role of H3K27 acetylation in PRC2-mediated functions.
- Elisa Lavarone
- , Caterina M. Barbieri
- & Diego Pasini
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Article
| Open AccessRdDM-independent de novo and heterochromatin DNA methylation by plant CMT and DNMT3 orthologs
Whether plants have true DNMT3 orthologs and their role in establishing DNA methylation are still unclear. Here, the authors show that DNMT3s are persistent through plant evolution and mediates both de novo and heterochromatin DNA methylation in the early divergent land plant Physcomitrella patens.
- Rafael Yaari
- , Aviva Katz
- & Nir Ohad
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Article
| Open AccessMultiplexed Cas9 targeting reveals genomic location effects and gRNA-based staggered breaks influencing mutation efficiency
Designing effective genome engineering strategies requires an understanding of the impact that genomic locus has on CRISPR-Cas9 activity. Here the authors use TRIP integrations to profile editing outcomes genome-wide and observe that gRNA sequence influences the structure of the double strand break.
- Santiago Gisler
- , Joana P. Gonçalves
- & Maarten van Lohuizen