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| Open AccessMammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.
- Vrutant V. Shah
- , Aundrietta D. Duncan
- & Michelle Craig Barton
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Article
| Open AccessVariant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes
Polycomb repressive complexes (PRC1 and PRC2) repress genes that are crucial for development via epigenetic modifications; however, their role in differentiation is not well known. Here the authors reveal that a PCGF1-containing PRC1 variant facilitates exit from pluripotency by downregulating target genes and recruiting PRC2.
- Hiroki Sugishita
- , Takashi Kondo
- & Haruhiko Koseki
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Article
| Open AccessLocus specific epigenetic modalities of random allelic expression imbalance
Some autosomal genes are expressed in a random monoallelic manner, but its extent and mechanisms have remained unclear. Here the authors show robust monoallelic expression in cell lines and mice, where the silent allele can be reexpressed using epidrugs. Further, they find these genes display various modalities of allelic expression with different degrees of allelic imbalance.
- Lucile Marion-Poll
- , Benjamin Forêt
- & Edith Heard
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Article
| Open AccessThe concurrence of DNA methylation and demethylation is associated with transcription regulation
The global pattern of the mammalian methylome is formed by changes in methylation and demethylation. Here the authors describe a metric methylation concurrence that measures the ratio of unmethylated CpGs inside the partially methylated reads and show that methylation concurrence is associated with epigenetically regulated tumour suppressor genes.
- Jiejun Shi
- , Jianfeng Xu
- & Wei Li
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Article
| Open AccessGenome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk
The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.
- Kira A. Perzel Mandell
- , Nicholas J. Eagles
- & Andrew E. Jaffe
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Article
| Open AccessPlacental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth
Maternal smoking during pregnancy contributes to poor birth outcomes. Here the authors perform a meta-analysis of the associations between maternal smoking during pregnancy and placental DNA methylation and identify links between these and poor birth outcomes, which may better inform the mechanisms through which smoking impacts placental function and fetal growth.
- Todd M. Everson
- , Marta Vives-Usano
- & Mariona Bustamante
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Article
| Open AccessNuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity
The histone acetyltransferase p300 mostly localizes to active chromatin; however, some repressed genes marked with H3K27me3 are also bound by p300. Here the authors show p300 is capable of phase separation, which relies on its catalytic core, and that p300 catalytic activity is decreased in phase-separated droplets that co-localize with H3K27me3-marked chromatin.
- Yi Zhang
- , Kyle Brown
- & Tatiana G. Kutateladze
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Article
| Open AccessPALI1 facilitates DNA and nucleosome binding by PRC2 and triggers an allosteric activation of catalysis
The polycomb repressive complex 2 (PRC2) is a histone methyltransferase regulating cell differentiation and identity. Here, the authors show that the vertebrate-specific PRC2 accessory subunit PALI1 facilitates substrate binding by the complex and elucidate the allosteric mechanism of PALI1- mediated PRC2 activation.
- Qi Zhang
- , Samuel C. Agius
- & Chen Davidovich
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Article
| Open AccessFunctional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome
Germline mutations in the DNMT3A gene can cause an overgrowth syndrome associated with behavioural and hematopoietic phenotypes. Here the authors describe a mouse model of this syndrome that recapitulates many of these features, including conserved alterations in DNA methylation in the blood cells of both species.
- Amanda M. Smith
- , Taylor A. LaValle
- & Timothy J. Ley
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Article
| Open AccessA machine learning approach to brain epigenetic analysis reveals kinases associated with Alzheimer’s disease
Array-based epigenome-wide association studies only test about 2% of the CpG sites in the genome. Here, the authors describe EWASplus, a supervised machine learning strategy that extends EWAS coverage to the entire genome, and use it to identify novel brain CpGs associated with Alzheimer’s disease.
- Yanting Huang
- , Xiaobo Sun
- & Zhaohui S. Qin
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Article
| Open AccessNeonatal thyroxine activation modifies epigenetic programming of the liver
Whether thyroid hormones affect gene expression via DNA methylation is not well known. Here the authors show that type 2 deiodinase (D2) converts T4 to produce T3, which prevents DNA methylation of discrete areas in the neonatal liver. In the absence of D2, DNA methylation occurs and is associated with reduced chromatin accessibility in promoters and enhancers and affects gene expression.
- Tatiana L. Fonseca
- , Tzintzuni Garcia
- & Antonio C. Bianco
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| Open AccessReactivation of a developmentally silenced embryonic globin gene
Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.
- Andrew J. King
- , Duantida Songdej
- & Christian Babbs
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Article
| Open AccessEarly-life social experience affects offspring DNA methylation and later life stress phenotype
Early social experience can alter epigenetic patterns and stress responses later in life. A study on wild spotted hyenas finds that maternal care and social connections after leaving the den influence DNA methylation and contribute to a developmentally plastic stress response.
- Zachary M. Laubach
- , Julia R. Greenberg
- & Wei Perng
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Article
| Open AccessComplete loss of H3K9 methylation dissolves mouse heterochromatin organization
Histone H3K9 methylation (H3K9me) states define repressed chromatin in eukaryotic cells. Here the authors reveal complete loss of all H3K9me in mammalian cells through successive deletion of H3K9 methyltransferase genes that results in the dissolution of heterochromatin and the derepression of nearly all repeat families.
- Thomas Montavon
- , Nicholas Shukeir
- & Thomas Jenuwein
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Article
| Open AccessLarge parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects
A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.
- Xing Jian
- & Gary Felsenfeld
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Article
| Open AccessArabidopsis MORC proteins function in the efficient establishment of RNA directed DNA methylation
MORC ATPases are required for transposable element silencing and heterochromatin condensation in plants and animals. Here the authors show that Arabidopsis MORCs colocalize with sites of RNA-directed DNA methylation and provide evidence that they act as molecular tethers to efficiently establish DNA methylation.
- Yan Xue
- , Zhenhui Zhong
- & Steven E. Jacobsen
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Article
| Open AccessEpigenetic memories and the evolution of infectious diseases
The virulence of some infectious diseases seems to depend on the sex of the host the infection came from, as well as that of the current host. Here, McLeod et al. develop an epidemiological model to investigate the evolution of virulence when pathogens can retain epigenetic memories of their previous host.
- David V. McLeod
- , Geoff Wild
- & Francisco Úbeda
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Article
| Open AccessTissue-specific 5-hydroxymethylcytosine landscape of the human genome
Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues and found 5hmC shows tissue-specific patterns.
- Bo He
- , Chao Zhang
- & Chengqi Yi
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| Open AccessMating can initiate stable RNA silencing that overcomes epigenetic recovery
Stable epigenetic changes are relatively rare. Here the authors report that mating induces stable silencing of a single-copy transgene in C. elegans. Components of small RNA silencing are required for this stable silencing.
- Sindhuja Devanapally
- , Pravrutha Raman
- & Antony M. Jose
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Article
| Open AccessEZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer
Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity.
- Marita Zoma
- , Laura Curti
- & Giuseppina M. Carbone
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Article
| Open AccessChromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver
Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.
- Chi Zhang
- , Filippo Macchi
- & Kirsten C. Sadler
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Article
| Open AccessRedirected nuclear glutamate dehydrogenase supplies Tet3 with α-ketoglutarate in neurons
α-ketoglutarate (αKG) is an intermediate in the tricarboxylic acid cycle that is required in the nucleus for genomic DNA demethylation by Tet3. Here, the authors show that the enzyme glutamate dehydrogenase, which converts glutamate to αKG, is redirected from the mitochondria to the nucleus.
- Franziska R. Traube
- , Dilara Özdemir
- & Thomas Carell
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Article
| Open AccessHigh-resolution characterization of gene function using single-cell CRISPR tiling screen
Identifying functional domains and genetic regulatory mechanisms is essential for developing new therapies. Here the authors present sc-Tiling, single-cell high-density CRISPR tiling screening for functional domain characterization.
- Lu Yang
- , Anthony K. N. Chan
- & Chun-Wei Chen
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Article
| Open AccessA multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids
Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.
- Min-A Jhun
- , Michael Mendelson
- & Themistocles L. Assimes
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Article
| Open AccessNeuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders
The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.
- Benxia Hu
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open AccessEnvironmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus
Decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Here the authors provide evidence that environmental enrichment delays age-related DNA methylation alterations in the mouse hippocampus.
- Sara Zocher
- , Rupert W. Overall
- & Gerd Kempermann
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Article
| Open AccessGenomic imprinting in mouse blastocysts is predominantly associated with H3K27me3
In most mammals, imprinted genes contain epigenetic marks that differ in each parental genome and control their parent-of-origin-specific expression. Here, the authors map imprinted genes in mouse preimplantation embryos and find that imprinted gene expression in blastocysts is mainly dependent on Polycomb-mediated H3K27me3-associated gene silencing.
- Laura Santini
- , Florian Halbritter
- & Martin Leeb
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Article
| Open AccessA gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker
The role of promoters as potential insulator elements has been largely unexplored in mammals. Here the authors show that a single nucleotide variant in the α-globin locus forms a new promoter and acts as an orientation-dependent enhancer-blocking insulator element.
- Yavor K. Bozhilov
- , Damien J. Downes
- & Douglas R. Higgs
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Article
| Open AccessHakai is required for stabilization of core components of the m6A mRNA methylation machinery
The E3 ligase Hakai can interact with the m6A methylation machinery but its function is still unclear. Here, the authors show that Hakai is a conserved component of the m6A methyltransferase complex and provide functional and molecular insights into its role in regulating m6A levels in Drosophila.
- Praveen Bawankar
- , Tina Lence
- & Jean-Yves Roignant
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Article
| Open AccessDefective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker
Abnormal folate metabolism in mice results in transgenerational epigenetic inheritance of congenital malformations. Here, the authors provide evidence that defective folate metabolism causes germline epigenetic instability and observe multigenerational misexpression of Hira in embryos, implicating Hira transcript levels as a biomarker of maternal phenotypic inheritance.
- Georgina E. T. Blake
- , Xiaohui Zhao
- & Erica D. Watson
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Article
| Open AccessIntegrated analysis of Xist upregulation and X-chromosome inactivation with single-cell and single-allele resolution
X-chromosome inactivation (XCI) ensures dosage compensation between the sexes. Here the authors perform allele-specific single-cell RNA sequencing in differentiating mouse embryonic stem cells to provide a detailed profile of the onset of XCI.
- Guido Pacini
- , Ilona Dunkel
- & Edda G. Schulz
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Article
| Open AccessMapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas
Gliomas are tumors often associated with epigenetics-related gene deregulation. Here the authors reveal an atlas of active enhancers and promoters in benign and malignant gliomas by performing whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples.
- Karolina Stępniak
- , Magdalena A. Machnicka
- & Bartek Wilczyński
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| Open AccessE2F6 initiates stable epigenetic silencing of germline genes during embryonic development
DNA methylation targets CpG island promoters of germline genes to repress their expression in mouse somatic cells. Here the authors show that a transcription factor E2F6 is required to target CpG island DNA methylation and epigenetic silencing to germline genes during early mouse development.
- Thomas Dahlet
- , Matthias Truss
- & Michael Weber
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Article
| Open AccessA meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
Although epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, previous studies have been limited in sample size and brain region used. Here, the authors combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differentially methylated loci across cortex.
- Rebecca G. Smith
- , Ehsan Pishva
- & Katie Lunnon
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| Open AccessThe epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation
LSH/HELLS is a chromatin remodeler promoting incorporation of histone variant macroH2A. Here the authors reveal a role for LSH in genome stability, in protecting nascent DNA at stalled forks mediated by macroH2A deposition and RAD51 filament formation.
- Xiaoping Xu
- , Kai Ni
- & Kathrin Muegge
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Article
| Open AccessChromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation
Both A/B compartments and TADs are thought to be absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, the authors characterise gene reactivation, chromatin opening and chromosome topology during X-reactivation, observe A/B-like compartments on the inactive X that guide TAD formation independently of transcription during X-reactivation.
- Moritz Bauer
- , Enrique Vidal
- & Bernhard Payer
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Article
| Open AccessH3K27me3 demethylases alter HSP22 and HSP17.6C expression in response to recurring heat in Arabidopsis
Acclimation to high temperature increases tolerance of heat shock in plants. Here the authors show that JUMONJI H3K27me3 demethylases are needed for heat acclimation in Arabidopsis and act at loci encoding HEAT SHOCK PROTEINS to facilitate induction upon heat stress.
- Nobutoshi Yamaguchi
- , Satoshi Matsubara
- & Toshiro Ito
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Article
| Open AccessHeteromeric HSFA2/HSFA3 complexes drive transcriptional memory after heat stress in Arabidopsis
Moderate heat stress primes plants to acquire tolerance to subsequent, more severe heat stress. Here the authors show that the HSFA3 transcription factor forms a heteromeric complex with HSFA2 to sustain activated transcription of genes required for acquired thermotolerance by promoting H3K4 hyper-methylation.
- Thomas Friedrich
- , Vicky Oberkofler
- & Isabel Bäurle
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Article
| Open AccessHIRA stabilizes skeletal muscle lineage identity
The epigenetic mechanisms coordinating the maintenance of adult cellular lineages remain poorly understood. Here the authors demonstrate that HIRA, a H3.3 histone chaperone, establishes the chromatin landscape required for skeletal muscle cell identity.
- Joana Esteves de Lima
- , Reem Bou Akar
- & Frédéric Relaix
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Article
| Open AccessHigh throughput screening identifies SOX2 as a super pioneer factor that inhibits DNA methylation maintenance at its binding sites
The functional relevance of epigenetic modifications on transcription regulation has been an important question since their discovery. Here, the authors investigate the effect of DNA methylation on Pioneer Transcription Factor (PF) binding and distinguish between PFs that protect their binding sites from methylation and those that bind to methylated DNA and induce DNA demethylation.
- Ludovica Vanzan
- , Hadrien Soldati
- & Rabih Murr
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Article
| Open AccessTET1-mediated DNA hydroxymethylation regulates adult remyelination in mice
Myelin formation is regulated by epigenetic mechanisms and ensures proper neuronal function during development and after demyelination. Here, the authors show that TET1, a DNA hydroxymethylase, regulates myelin repair in adult mice, but is defective with aging.
- Sarah Moyon
- , Rebecca Frawley
- & Patrizia Casaccia
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Article
| Open AccessTemporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer
The heterogeneity of tumor evolution from AR-positive, adenocarcinoma to AR-negative, neuroendocrine prostate cancer (NEPC) is not fully characterized. Here the authors generate a mouse model to show that Rb1 loss and MYCN overexpression accelerates the progression to AR-negative NEPC and identify emergence of distinct subpopulations of NEPC cells.
- Nicholas J. Brady
- , Alyssa M. Bagadion
- & David S. Rickman
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Article
| Open AccessA histone H3K4me1-specific binding protein is required for siRNA accumulation and DNA methylation at a subset of loci targeted by RNA-directed DNA methylation
In plants, RNA-directed DNA methylation (RdDM) is a de novo DNA methylation pathway that is responsible for transcriptional silencing of repetitive elements. Here, the authors characterized a new RdDM factor, RDM15, and show that it is required for RdDM-dependent DNA methylation and siRNA accumulation at a subset of RdDM target loci.
- Qingfeng Niu
- , Zhe Song
- & Zhaobo Lang
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Article
| Open AccessDynamic methylation of histone H3K18 in differentiating Theileria parasites
Post-translational modifications (PTM) of histones are important for epigenetic regulation in mammals. Here, Cheeseman et al. report dynamic changes in H3K18 PTM during the differentiation stages of Theileria parasites and they identify a SET-domain methyltransferase (TaSETup1) as the relevant enzyme promoting this modification.
- Kevin Cheeseman
- , Guillaume Jannot
- & Jonathan B. Weitzman
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Article
| Open AccessImpact of DNA methylation on 3D genome structure
Multi-layered epigenetic regulation in higher eukaryotes makes it challenging to disentangle the individual effects of modifications on chromatin structure and function. Here, the authors expressed mammalian DNA methyltransferases in yeast, which have no DNA methylation, to show that methylation has intrinsic effects on chromatin structure.
- Diana Buitrago
- , Mireia Labrador
- & Modesto Orozco
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Article
| Open AccessEctopic targeting of CG DNA methylation in Arabidopsis with the bacterial SssI methyltransferase
The ability to target DNA methylation to specific loci is important for both basic and applied research. Here, the authors fuse CG-specific methyltransferase SssI with an artificial zinc finger protein for DNA methylation targeting and show the chromatin features favorable for efficient gain of methylation.
- Wanlu Liu
- , Javier Gallego-Bartolomé
- & Steven E. Jacobsen
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Article
| Open AccessHigh-throughput single-cell chromatin accessibility CRISPR screens enable unbiased identification of regulatory networks in cancer
Transcription factor binding dynamics can drive epigenetic states, enabling a diversity of phenotypes. Here the authors present Spear-ATAC to quantify and map perturbations to chromatin accessibility in single cells at high throughput.
- Sarah E. Pierce
- , Jeffrey M. Granja
- & William J. Greenleaf
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| Open AccessEpigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption
While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.
- Irma Karabegović
- , Eliana Portilla-Fernandez
- & Mohsen Ghanbari
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Article
| Open AccessPHC1 maintains pluripotency by organizing genome-wide chromatin interactions of the Nanog locus
Phc1 is a subunit of the polycomb repressive complex 1 (PRC1), which represses gene expression during development. Here the authors show that Phc1 acts independently from PRC1 to activate Nanog transcription by stabilizing genome-wide chromatin interactions of the Nanog locus, and in turn stabilize pluripotency.
- Li Chen
- , Qiaoqiao Tong
- & Junfeng Ji