Epigenetics

  • Article
    | Open Access

    Here, the authors introduce Cell Heterogeneity–Adjusted cLonal Methylation (CHALM) as a methylation quantification method that considers the heterogeneity of sequenced bulk cells. They apply CHALM to methylation datasets to detect differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.

    • Jianfeng Xu
    • , Jiejun Shi
    •  & Wei Li
  • Article
    | Open Access

    The role of BRD4 and Mediator in regulating enhancer-promoter interactions is poorly understood. Here the authors find that treatment with BET inhibitors or pharmacological degradation of BRD4 disrupts transcription while having very little effect on enhancer-promoter interactions.

    • Nicholas T. Crump
    • , Erica Ballabio
    •  & Thomas A. Milne
  • Article
    | Open Access

    Genomes are partitioned into topologically associating domains (TADs). Here the authors present single-nucleus Hi-C maps in Drosophila at 10 kb resolution, demonstrating the presence of chromatin compartments in individual nuclei, and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which resembles population TAD profiles.

    • Sergey V. Ulianov
    • , Vlada V. Zakharova
    •  & Sergey V. Razin
  • Article
    | Open Access

    Dynamic arrangement of epigenetic modifications such as repressive H3K27 methylation is essential for zygote development. Here the authors show that establishment of genome-wide H3K27me3 in zygotes requires EZH2, that EZH1 partially compensates for EZH2 loss, and that EHMT1 is involved in H3K27me2 establishment.

    • Tie-Gang Meng
    • , Qian Zhou
    •  & Qing-Yuan Sun
  • Article
    | Open Access

    Acidothermus cellulolyticus CRISPR-Cas9 (AceCas9) is a Type II-C enzyme that cleaves DNA in a Protospacer Adjacent Motif (PAM) methylation sensitive fashion. Biochemical analysis and crystal structures of AceCas9 in complex with sgRNA and DNA bearing the correct and incorrect PAM offer insight into the structural basis for the recognition of PAM and its methylation.

    • Anuska Das
    • , Travis H. Hand
    •  & Hong Li
  • Article
    | Open Access

    Strong transgene suppression has been observed in Chlamydomonas reinhardtii, but the underlying mechanism is unknown. Here, the authors identify a sirtuin-type histone deacetylase that selectively acts on transgenic DNA to repress gene expression by assembling a repressive chromatin structure composed of deacetylated histones.

    • Juliane Neupert
    • , Sean D. Gallaher
    •  & Ralph Bock
  • Article
    | Open Access

    Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.

    • Sanja Pajovic
    • , Robert Siddaway
    •  & Cynthia Hawkins
  • Article
    | Open Access

    Histone 3 Lys 27 trimethylation (H3K27me3) mediates epigenetic silencing of gene expression. Here, Zhang et al. show that in Arabidopsis, the BAH-domain H3K27me3-reader protein AIPP3 forms a complex with PHD proteins and CPL2, a plant-specific Pol II phosphatase, to inhibit Pol II activity by dephosphorylation.

    • Yi-Zhe Zhang
    • , Jianlong Yuan
    •  & Cheng-Guo Duan
  • Article
    | Open Access

    Chromatin structure and topology play important roles in the regulation of gene expression. Here the authors study the spatio-temporal re-organization of promoter-enhancer interactions in pluripotent ES and skeletal muscle stem cells and the corresponding impact on gene expression as a consequence of myogenic commitment and differentiation.

    • Nan Zhang
    • , Julen Mendieta-Esteban
    •  & Brian David Dynlacht
  • Article
    | Open Access

    DNA 5-hydroxymethylcytosine (5hmC) modification is associated with gene transcription and used as a mark of mammalian development. Here the authors report a comprehensive 5hmC tissue map and analysis of 5hmC genomic distributions in 19 human tissues derived from 10 organ systems, thus providing insights into the role of 5hmC in tissue-specific development.

    • Xiao-Long Cui
    • , Ji Nie
    •  & Chuan He
  • Article
    | Open Access

    Duchenne muscular dystrophy (DMD) is characterised by progressive muscle degeneration. Here, the authors show that the BET protein BRD4 is increased in the muscle of DMD mouse models, and that pharmacological inhibition of BRD4 leads to reduced muscle pathology in mice, by modulating NADPH oxidase expression.​

    • Marco Segatto
    • , Roberta Szokoll
    •  & Giuseppina Caretti
  • Article
    | Open Access

    Firre encodes a lncRNA involved in nuclear organization in mammals. Here, the authors find that allelic deletion of Firre on the active X chromosome (Xa) results in dose-dependent loss of histone H3K27me3 on the inactive X chromosome (Xi), along with other trans-acting effects, including disruption of the perinuclear location and minor dysregulation of gene expression.

    • He Fang
    • , Giancarlo Bonora
    •  & Christine M. Disteche
  • Article
    | Open Access

    Active and passive demethylation pathways have been implicated in the genome-wide erasure of 5mC accompanying mammalian preimplantation development. Here the authors reveal a recently evolved, mammalian-specific pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation.

    • Christopher B. Mulholland
    • , Atsuya Nishiyama
    •  & Heinrich Leonhardt
  • Article
    | Open Access

    Hepatic lipogenesis is a tightly regulated process, which is elevated in obesity. Here the authors report that FGF15/19, bile acid-induced gut hormones, repress lipogenic genes in the late fed-state by activating small heterodimer partner (SHP) and promoting SHP-dependent recruitment of DNA methyltransferase DNMT3A to lipogenic genes.

    • Young-Chae Kim
    • , Sunmi Seok
    •  & Jongsook Kim Kemper
  • Review Article
    | Open Access

    Histone H2A monoubiquitination on lysine 119 in vertebrate and lysine 118 in Drosophila (H2Aub) is an epigenomic mark usually associated with gene repression by Polycomb group factors. Here the authors review the current knowledge on the deposition and removal of H2Aub, its function in transcription and other DNA-associated processes as well as its relevance to human disease.

    • Haithem Barbour
    • , Salima Daou
    •  & El Bachir Affar
  • Article
    | Open Access

    Epigenetically altered genes can have a key role in cancer pathobiology but epigenetic signatures that distinguish oncogenes are not yet known. Here, the authors identify broad genic repression domains, defined by widespread H3K27me3 modification, as an epigenetic signature to provide mutation-independent information for discovery of potential oncogenes.

    • Dongyu Zhao
    • , Lili Zhang
    •  & Kaifu Chen
  • Article
    | Open Access

    The paternal genome in mice undergoes widespread DNA methylation loss post-fertilization. Here, the authors apply allele-specific analysis of WGBS data to show that a number of genomic regions are simultaneously de novo methylated on the paternal genome dependent on maternal DNMT3A activity, which induces transcriptional silencing of this allele in the early embryo.

    • Julien Richard Albert
    • , Wan Kin Au Yeung
    •  & Matthew Lorincz
  • Article
    | Open Access

    The histone variant mutation H3.3-G34W occurs in the majority of giant cell tumor of bone (GCTB). By profiling patient-derived GCTB tumor cells, the authors show that this mutation associates with epigenetic alterations in heterochromatic and bivalent regions that contribute to an impaired osteogenic differentiation and the osteolytic phenotype of GCTB.

    • Pavlo Lutsik
    • , Annika Baude
    •  & Christoph Plass
  • Article
    | Open Access

    The meiotic transmissibility and progeny phenotypic influence of graft-mediated epigenetic changes remain unclear. Here, the authors use the msh1 mutant in the rootstock to trigger heritable enhanced growth vigor in Arabidopsis and tomato, and show it is associated with the RNA-directed DNA methylation pathway.

    • Hardik Kundariya
    • , Xiaodong Yang
    •  & Sally A. Mackenzie
  • Article
    | Open Access

    Allele-specific measurements can reveal differences in DNA methylation between homologous alleles associated with changes in genetic sequence. Here, the authors develop a method for detecting allele specific methylation events within haplotypes of linked SNPs, compare it with existing methods, and show it identifies haplotypes for which the genetic variant carries significant information about the methylation state of the allele of origin.

    • J. Abante
    • , Y. Fang
    •  & J. Goutsias
  • Article
    | Open Access

    Previous work suggested that histone demethylase JMJD3 is detrimental to somatic cell reprogramming. Here, the authors show that while JMJD3 has a context-independent detrimental effect on early stages of reprogramming, during late stages it activates epithelial and pluripotency genes together with Klf4.

    • Yinghua Huang
    • , Hui Zhang
    •  & Baoming Qin
  • Article
    | Open Access

    Chromatin state underlies cellular function, and transcription factor binding patterns along with epigenetic marks define chromatin state. Here the authors show that the histone chaperone ANP32E functions through regulation of H2A.Z to restrict genome-wide chromatin accessibility and to inhibit gene transcriptional activation.

    • Kristin E. Murphy
    • , Fanju W. Meng
    •  & Patrick J. Murphy
  • Article
    | Open Access

    The HUSH complex plays a key role in controlling transcription of viruses and transposable elements. Here, the authors define the biochemical basis of HUSH assembly and show that the TASOR subunit contains a pseudo-PARP domain critical for HUSH-dependent transgene repression and H3K9me3 deposition over targets genome wide.

    • Christopher H. Douse
    • , Iva A. Tchasovnikarova
    •  & Yorgo Modis
  • Article
    | Open Access

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with repetitive and restrictive behaviours. Here the authors integrate mRNA expression, miRNA expression, DNA methylation, and histone acetylation datasets from a collection of post mortem brain tissues and identify a convergent molecular subtype of ASD.

    • Gokul Ramaswami
    • , Hyejung Won
    •  & Daniel H. Geschwind
  • Article
    | Open Access

    Polycomb (PcG) and Trithorax (TrxG) group regulate several hundred target genes with important roles in development and disease. Here the authors combine experiment and theory to provide evidence that the Polycomb/Trithorax system has the potential for a rich repertoire of regulatory modes beyond simple epigenetic memory.

    • Jeannette Reinig
    • , Frank Ruge
    •  & Leonie Ringrose
  • Article
    | Open Access

    Preimplantation embryos undergo extensive transcriptomic and epigenomic remodeling. Here the authors assay open chromatin in bovine oocytes, embryos, and embryonic stem cells, and compare the transcriptomes and epigenomes of cattle, human and mouse embryos, revealing species-specific regulation of genome activation.

    • Michelle M. Halstead
    • , Xin Ma
    •  & Pablo J. Ross
  • Article
    | Open Access

    Mutations in RAS-MAPK pathway genes are implicated in Noonan-spectrum, yet up to 20% of cases have unknown cause. Here, the authors identify RREB1 underlying a 6p microdeletion RASopathy-like syndrome and show that RREB1, SIN3A and KDM1A form a transcriptional repressive complex to control methylation of MAPK pathway genes.

    • Oliver A. Kent
    • , Manipa Saha
    •  & Robert Rottapel
  • Article
    | Open Access

    Epigenetic mechanisms have emerged as contributors to the molecular impairments caused by exposure to environmental factors such as abused substances. Here the authors perform epigenetic profiling of the striatum and identify the tyrosine kinase FYN is an important driver of neurodegenerative-like pathology and drug-taking behaviour.

    • Gabor Egervari
    • , Diana Akpoyibo
    •  & Yasmin L. Hurd
  • Article
    | Open Access

    Although Huntington’s disease (HD) is a well-studied genetic disorder, less is known about the epigenetic changes underlying it. Here, the authors characterize DNA methylation levels in tissues from patients, a mouse huntingtin (Htt) gene knock-in model, and a transgenic HTT sheep model, and provide evidence that HD is accompanied by DNA methylation changes in these three species.

    • Ake T. Lu
    • , Pritika Narayan
    •  & Steve Horvath
  • Article
    | Open Access

    Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Here the authors report that homozygous dnmt1 mutant zebrafish are essentially normal, with the exception of impaired lymphopoiesis, with impaired larval (but not adult) T cell development being transmitted to subsequent generations by genotypically wildtype fish.

    • Norimasa Iwanami
    • , Divine-Fondzenyuy Lawir
    •  & Thomas Boehm
  • Article
    | Open Access

    S. cerevisiae TBP associated factor 14 (Taf14) is a transcriptional regulator that interacts with multiple nuclear complexes. Here, the authors report that the extra-terminal domain of Taf14 (Taf14ET) recognizes a common motif in various transcriptional coactivator proteins and they solve the NMR structure of Taf14ET bound the ET-binding motif of Sth1, the catalytic subunit of the RSC (Remodel the Structure of Chromatin) complex, and furthermore show that Taf14ET undergoes liquid-liquid phase separation, which is enhanced by Taf14 interaction partners.

    • Guochao Chen
    • , Duo Wang
    •  & Yong Chen
  • Article
    | Open Access

    Genetic variants in KIF3A are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower KIF3A expression. Mice with epidermis-specific loss of Kif3a show disrupted skin barrier homeostasis and increased AD susceptibility.

    • Mariana L. Stevens
    • , Zhonghua Zhang
    •  & Gurjit K. Khurana Hershey
  • Article
    | Open Access

    Reconstructing the early molecular evolution of animals requires genomic resources for non-bilaterian animals. Here, the authors present the chromosome-level genome of a freshwater sponge together with analyses of its genome architecture, methylation, developmental gene expression, and microbiome.

    • Nathan J. Kenny
    • , Warren R. Francis
    •  & Sally P. Leys
  • Article
    | Open Access

    Epigenetic reprogramming is a hallmark of cancer. Here the authors find that resetting primed human embryonic stem cells to naïve state results in the acquisition of a DNA methylation landscape that mirrors the cancer DNA methylome and provides evidence that the transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories.

    • Hemalvi Patani
    • , Michael D. Rushton
    •  & Gabriella Ficz
  • Article
    | Open Access

    In mammals, DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B. Here the authors report the crystal structures of DNMT3B in complex with both CpG and CpA DNA, providing insight into the substrate-recognition mechanism underpinning the divergent genomic methylation activities of DNMT3A and DNMT3B.

    • Linfeng Gao
    • , Max Emperle
    •  & Jikui Song
  • Article
    | Open Access

    The molecular and physical mechanisms underlying chromatin folding at the single DNA molecule level remain poorly understood. Here, the authors use polymer modeling to investigate the conformations of two 2Mb-wide DNA loci in normal and cohesin depleted cells, and provide evidence that the architecture of the studied loci is controlled by a thermodynamics mechanism of polymer phase separation whereby chromatin self-assembles in segregated globules.

    • Mattia Conte
    • , Luca Fiorillo
    •  & Mario Nicodemi
  • Article
    | Open Access

    Epigenetic regulation can silence transposons and maintain gene expression. Here the authors survey Arabidopsis mutants defective in epigenetic regulation and show ectopic activation of thousands of cryptic TSSs and altered expression of nearby genes demonstrating the importance of suppressing spurious transcription.

    • Ngoc Tu Le
    • , Yoshiko Harukawa
    •  & Hidetoshi Saze
  • Article
    | Open Access

    Protein arginine deiminase 4 (PAD4) facilitates the posttranslational citrullination of histones H3 and H4. Here, the authors provide evidence that PAD4 antagonizes histone methylglyoxal-glycation by rewriting the glycated arginine into citrulline and protecting the reactive sites from further glycation.

    • Qingfei Zheng
    • , Adewola Osunsade
    •  & Yael David
  • Article
    | Open Access

    De novo DNA methylation is carried out by DNMT3A and DNMT3B, but the distinct functions of these two enzymes is poorly understood. Here the authors present a comprehensive, genome-wide identification of target sites for de novo DNA methylation by the DNMT3A and DNMT3B in mouse ES cells and embryos, identifying unique de novo DNA methylation target sites for both DNMT3 enzymes.

    • Masaki Yagi
    • , Mio Kabata
    •  & Yasuhiro Yamada
  • Article
    | Open Access

    MeCP2 is a transcriptional repressor and associates with nucleosomes. Here the authors show interaction of MeCP2 and H3K27me3 by biochemical assay and chromatin immunoprecipitation sequencing analysis.

    • Wooje Lee
    • , Jeeho Kim
    •  & Qizhi Gong
  • Article
    | Open Access

    CENP-A is a stable centromere mark, although active transcription poses a potential threat for retaining CENP-A through chromatin remodeling and nucleosome eviction. Here, the authors show that maintenance of the centromeric mark is preserved by Spt6, which recycles CENP-A nucleosomes.

    • Georg O. M. Bobkov
    • , Anming Huang
    •  & Patrick Heun