Gene silencing

  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Pyruvate kinase phosphorylates histone H3T11 (H3pT11) and represses gene expression by forming a large complex SESAME (Serine-responsive SAM-containing Metabolic Enzyme). Here the authors show that SESAME-catalyzed H3pT11 regulates telomere silencing by promoting Sir2 binding at telomeres and preventing autophagy-mediated Sir2 degradation.

    • Shihao Zhang
    • , Xilan Yu
    •  & Shanshan Li
  • Article
    | Open Access

    Targeting chromatin regulators to a gene is emerging as powerful tool to control transcription. Here the authors demonstrate the use of nanobodies against chromatin regulators to control gene expression and epigenetic memory.

    • Mike V. Van
    • , Taihei Fujimori
    •  & Lacramioara Bintu
  • 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

    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 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

    Mediator is a multiprotein complex required to activate gene transcription by RNAPII. Here, the authors report that MED12 and MED13 are conditional positive regulators that facilitate the expression of genes depleted in active chromatin marks and the induction of gene expression in response to environmental stimuli in Arabidopsis.

    • Qikun Liu
    • , Sylvain Bischof
    •  & Steven E. Jacobsen
  • Article
    | Open Access

    In fission yeast, several lncRNAs act in cis to regulate expression of adjacent genes. Here, the authors show that the conserved Pir2ARS2 protein is targeted, along with splicing factors, to cryptic introns in lncRNAs and recruits effectors, including RNAi machinery, for gene repression.

    • Gobi Thillainadesan
    • , Hua Xiao
    •  & Shiv I. S. Grewal
  • Article
    | Open Access

    ATRX is an RNA binding protein that mediates targeting of polycomb repressive complex 2 (PRC2) to genomic sites. Here the authors identify the RNA binding region and show that the RNA binding is required for ATRX localization and for its recruitment of PRC2 to a subset of polycomb targets.

    • Wenqing Ren
    • , Nicole Medeiros
    •  & Kavitha Sarma
  • Article
    | Open Access

    RNA is implicated in the targeting and function of Polycomb Group (PcG) chromatin regulators. Here the authors show that R-loops, three-stranded nucleic acid structures formed by DNA and RNA, are formed at some PcG binding sites in flies, as they are in mammals. Fly PRC2 can drive formation of RNA-DNA hybrids in vitro.

    • Célia Alecki
    • , Victoria Chiwara
    •  & Nicole J. Francis
  • Article
    | Open Access

    In Brassicaceae, interaction between the pollen-derived peptide ligand SP11 and the pistil-expressed receptor kinase SRK leads to self-incompatibility. Here the authors provide evidence that in Arabidopsis dominant self-compatibility inducers evolved at least twice via insertion of inverted repeats in the SRK locus.

    • Sota Fujii
    • , Hiroko Shimosato-Asano
    •  & Seiji Takayama
  • Article
    | Open Access

    RNA-directed DNA methylation (RdDM) is thought to silence newly inserted transposable elements (TEs) with RNA-independent mechanisms becoming more prominent as TEs age. Here, the authors show that RdDM continues to silence the oldest intact distal TEs in tomato and Arabidopsis suggesting a second, later phase of RdDM.

    • Zhengming Wang
    •  & David C. Baulcombe
  • Article
    | Open Access

    XACT is a primate-specific TE-derived lncRNA that coats active X chromosomes in pluripotent cells and may contribute to species-specific regulation of X chromosome inactivation. Here, the authors investigate TEs associated with the XACT locus and identify a critical enhancer for its regulation, which evolved from an ancestral group of mammalian endogenous retroviruses, prior to the emergence of XACT.

    • Miguel Casanova
    • , Madeleine Moscatelli
    •  & Claire Rougeulle
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Eukaryotic genomes are segregated into euchromatin and heterochromatin. Here the authors show that heterochromatin establishment during zebrafish embryo development is controlled by zygotic transcription of miR-430 and subsequent degradation of maternal transcripts encoding the chromatin remodeling protein Smarca2.

    • Kathrin Laue
    • , Srivarsha Rajshekar
    •  & Mary G. Goll
  • Article
    | Open Access

    Tight regulation of retrotransposons such as endogenous retroviruses (ERVs) is essential for genome and transcriptome integrity. Here, the authors show that the ATPase function of the chromatin remodeler SMARCAD1 facilitates the binding of KAP1 to ERVs and is required for their repression in embryonic stem cells.

    • Parysatis Sachs
    • , Dong Ding
    •  & Jacqueline E. Mermoud
  • Article
    | Open Access

    The mechanisms of paternal epigenetic inheritance and its influence on offspring are still poorly understood. Here the authors provide evidence that in C. elegans, sperm-inherited chromatin states influence transcription and cell identity in the germ cells of offspring.

    • Kiyomi Raye Kaneshiro
    • , Andreas Rechtsteiner
    •  & Susan Strome
  • Article
    | Open Access

    Lysine27-to-methionine mutations in histone H3 genes (H3K27M) occur in a subgroup of gliomas and decrease genome-wide H3K27 trimethylation. Here the authors utilise primary H3K27M tumour lines and isogenic CRISPR-edited controls and show that H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3.

    • Ashot S. Harutyunyan
    • , Brian Krug
    •  & Jacek Majewski
  • Article
    | Open Access

    Transcription factor (TF) networks are essential for the molecular identity of each cell type. Here, the authors show that TF Nanog utilises multiple molecular strategies to enhance embryonic stem cell self-renewal, which include regulation of chromatin accessibility in the presence of LIF or maintenance of H3K27me3 at developmental regulators in its absence.

    • Victor Heurtier
    • , Nick Owens
    •  & Pablo Navarro
  • Article
    | Open Access

    In fission yeast, Erh1, ortholog of human ERH, interacts with the YTH family RNA binding protein Mmi1 to form the Erh1-Mmi1 complex (EMC), which has been implicated in gene silencing. Here, the authors present the cocrystal structure of Erh1 homodimers interacting with Mmi1 and further characterise the role of EMC in facultative heterochromatin assembly and gene silencing.

    • Guodong Xie
    • , Tommy V. Vo
    •  & Shiv I. S. Grewal
  • Article
    | Open Access

    miRNAs have emerged as regulators of diverse biological processes including cancer. Here the authors present an extended pan-cancer analysis of the miRNAs in 15 epithelial cancers; integrating methylation, transcriptomic and mutation data they reveal alternative mechanisms of tumour suppressors’ regulation in absence of mutation, methylation or copy number alterations.

    • Andrew Dhawan
    • , Jacob G. Scott
    •  & Francesca M. Buffa
  • Article
    | Open Access

    Topoisomerases solve topological problems during DNA metabolism, but their role in RNA metabolism remains unclear. Here the authors provide evidence that in Drosophila, Topoisomerase 3β interacts biochemically and genetically with the RNAi-induced silencing complex (RISC) to promote heterochromatin formation and transcriptional silencing.

    • Seung Kyu Lee
    • , Yutong Xue
    •  & Weidong Wang
  • Article
    | Open Access

    Epigenetic regulation is critical for the maintenance of germ cell identity. Here the authors show that H3K9me3-mediated gene silencing is critical for repression of testis-specific transcription in Drosophila female germ cells, indicating H3K9me3 maintains female germ cell sexual identity.

    • Anne E. Smolko
    • , Laura Shapiro-Kulnane
    •  & Helen K. Salz
  • Article
    | Open Access

    Loss of Polycomb repressive complex 1 (PRC1) proteins usually results in both chromatin unfolding and ectopic transcription. Here, the authors analyze the temporal function of two PRC1 proteins during Drosophila embryogenesis and provide evidence that PRC1 maintains gene silencing by folding chromatin domains.

    • Thierry Cheutin
    •  & Giacomo Cavalli
  • Article
    | Open Access

    While a majority of histones are replaced by protamines during spermatogenesis, a small amount is retained in mammalian spermatozoa. Here the authors develop a method to purify histones from replacement-completed sperm (HRCS), completely solubilize histones from cross-linked HRCS without MNase digestion, and map histone-binding sites in these cells.

    • Keisuke Yoshida
    • , Masafumi Muratani
    •  & Shunsuke Ishii
  • Article
    | Open Access

    Polycomb-group proteins are key regulators of transcriptional programs that maintain cell identity. Here the authors provide evidence that PCGF5, a subunit of Polycomb Repressor Complex 1, is important for the differentiation of mouse embryonic stem cells towards a neural cell fate.

    • Mingze Yao
    • , Xueke Zhou
    •  & Hongjie Yao
  • Article
    | Open Access

    Previous studies suggest that DNA methylation is the main mechanism to silence endogenous retroviruses (ERVs) in somatic cells. Here the authors provide evidence that distinctive sets of ERVs are silenced by Setdb1 in different types of somatic cells, suggesting a general function in ERV silencing.

    • Masaki Kato
    • , Keiko Takemoto
    •  & Yoichi Shinkai
  • Article
    | Open Access

    Repression of gene transcription using CRISPR-Cas9 has been achieved in vitro but not for delivery into adult animal models. Here, the authors use AAV8 to deliver the transcriptional repressor dSaCas9KRAB to the cholesterol regulator Pcsk9, and show repression up to 24 weeks and reduced cholesterol levels in mice.

    • Pratiksha I. Thakore
    • , Jennifer B. Kwon
    •  & Charles A. Gersbach
  • Article
    | Open Access

    Microrchidia CW-type zinc finger protein 2 (MORC2) is an effector of epigenetic silencing by the human silencing hub (HUSH). Here the authors present the crystal structures of MORC2 and disease-causing MORC2 mutants and give mechanistic insights into how MORC2 mediates HUSH-dependent silencing.

    • Christopher H. Douse
    • , Stuart Bloor
    •  & Yorgo Modis
  • Article
    | Open Access

    CARM1 is an arginine methyltransferase often overexpressed in human cancer. Here, the authors show that EZH2 inhibition suppresses growth in CARM1-expressing epithelial ovarian cancer, and examine the mechanism of how CARM1 promotes EZH2-mediated tumor suppressor gene silencing.

    • Sergey Karakashev
    • , Hengrui Zhu
    •  & Rugang Zhang
  • Article
    | Open Access

    Plants use multiple cues to monitor seasonal temperatures. Here, the authors show that Arabidopsis requires not only prolonged cold, but the absence of temperature spikes above 15 °C to epigenetically silence FLC during winter.

    • Jo Hepworth
    • , Rea L. Antoniou-Kourounioti
    •  & Caroline Dean