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| Open AccessA SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer
POU2AF2 is a co-activator of POU2F3 in normal and neoplastic tuft cells, such as small cell lung cancer. Here, the authors report that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements.
- Aileen Szczepanski
- , Natsumi Tsuboyama
- & Lu Wang
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Article
| Open AccessKdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
Kdm1a is a histone demethylase implicated in intellectual disability. Here, the authors show that removing Kdm1a in neurons of the adult mouse forebrain disrupts silencing of nonneuronal genes and chromatin organization, emphasizing its role in preserving neuronal genome integrity.
- Beatriz del Blanco
- , Sergio Niñerola
- & Ángel Barco
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Article
| Open AccessNeuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes
Here, the authors identify neuron-specific miR-9 that potentially blocks HSV-1 neuronal replication by targeting host OCT-1 and ONECUT transcription factors involved in epigenetic activation of HSV-1 productive-cycle genes. Thus miR-9 promotes viral epigenetic silencing and latent infection in neurons.
- Yue Deng
- , Yuqi Lin
- & Dongli Pan
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Article
| Open AccessHRDE-2 drives small RNA specificity for the nuclear Argonaute protein HRDE-1
Argonaute proteins are loaded with small RNAs to confer target RNA specificity and proper gene silencing. Here, the authors establish that HRDE-2 recruits the unloaded nuclear Argonaute HRDE-1 to germ granules to facilitate correct small RNA loading.
- Shihui Chen
- & Carolyn M. Phillips
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Article
| Open AccessLoss of cohesin regulator PDS5A reveals repressive role of Polycomb loops
Through a genetic screen, the authors find that the cohesin regulator PDS5A is required for Polycomb target gene silencing. Derepression upon cohesin dysregulation is linked to loss of Polycomb loops without change in repressive chromatin domains.
- Daniel Bsteh
- , Hagar F. Moussa
- & Oliver Bell
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| Open AccessFunctional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells
RYBP and YAF2 are a pair of paralog subunits of variant PRC1. Here, authors show that RYBP decrease but YAF2 increase during mESC neural differentiation, and that they are not redundant but function differentially in regulating this differentiation.
- Yanjiang Liu
- , Gongcheng Hu
- & Hongjie Yao
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Article
| Open AccessSMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
Here the authors reveal that a neomorphic mutation in chromatin protein SMCHD1 enhances SMCHD1-mediated gene silencing, including at the FSHD disease-relevant locus, while depleting SMCHD1-mediated chromatin interactions, suggesting these SMCHD1 functions are unlinked.
- Andres Tapia del Fierro
- , Bianca den Hamer
- & Marnie E. Blewitt
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Article
| Open AccessYAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis
Small cell lung cancers (SCLC) have often inactivating mutations in RB1. In this study, the authors demonstrate that RB1 loss mediates low expression of YAP1 in SCLC tumors ultimately promoting metastasis and they propose to use benzamide family HDAC inhibitors to induce YAP1 expression for prevention of metastases.
- Zhengming Wu
- , Junhui Su
- & Kun-Liang Guan
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Article
| Open AccessThe MOM1 complex recruits the RdDM machinery via MORC6 to establish de novo DNA methylation
It has generally been considered that MOM1, a transcriptional silencing factor in plants, mediated silencing is independent or downstream of DNA methylation. Here, the authors show that MOM1 complex recruits the RdDM machinery through MORC6 to establish de novo DNA methylation in Arabidopsis.
- Zheng Li
- , Ming Wang
- & Steven E. Jacobsen
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Article
| Open AccessHistone H1 facilitates restoration of H3K27me3 during DNA replication by chromatin compaction
Liu et al. investigated the dynamic re-establishment of H3K27me3 on nascent DNA during DNA replication. They found H1-mediated chromatin compaction facilitates the propagation and restoration of H3K27me3 after DNA replication.
- Cuifang Liu
- , Juan Yu
- & Guohong Li
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Article
| Open AccessHistone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
The molecular mechanisms underlying androgen production in prostate cancer remain to be explored. Here, the authors reveal an epigenetic mark, K130Ac on H2A, following dual-phosphorylation on SREBP1 promoting de novo androgen synthesis to overcome the pharmacological inhibition of androgen synthesis.
- Thanh Nguyen
- , Dhivya Sridaran
- & Nupam P. Mahajan
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Article
| Open AccessPolycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors
Delineating the specific role of Polycomb Repressive Complex 2 (PRC2) in various cancer systems is desirable as inhibitors for EZH2 inhibitors are approved for some cancers. Here the authors show haplo- and full-insufficiency of EZH2 drive divergent phenotypes in lung cancer. 3D tumoroids recapitulate transcriptional profiles, including FOXP2 derepression, and drug responses of in vivo tumors.
- Fan Chen
- , Aria L. Byrd
- & Christine Fillmore Brainson
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Article
| Open AccessPCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment
Here the authors show that a Polycomb Repressive Complex 1 (PRC1) containing PCGF1 prevents excessive loading of transcriptional activators and chromatin remodelers on nascent DNA, allowing proper deposition of nucleosomes immediately after the passage of the DNA replication fork to optimize downstream chromatin configurations in hematopoietic stem and progenitor cells (HSPCs).
- Junichiro Takano
- , Shinsuke Ito
- & Tomokatsu Ikawa
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Article
| Open AccessActive DNA damage response signaling initiates and maintains meiotic sex chromosome inactivation
Here the authors show that active DNA damage response signaling is required both to initiate and maintain meiotic sex chromosome inactivation via a dynamic and reversible process.
- Hironori Abe
- , Yu-Han Yeh
- & Satoshi H. Namekawa
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Article
| Open AccessCK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site
Here the authors identify SUZ12 as a cellular substate of casein kinase 2 (CK2), and show this phosphorylation changes the active site structure of Polycomb repressive complex 2 (PRC2) and promotes PRC2 function in cell identity maintenance during stem cell differentiation.
- Lihu Gong
- , Xiuli Liu
- & Xin Liu
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Article
| Open AccessVAL1 acts as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC
Cold-induced silencing of Arabidopsis FLC requires the binding of VAL1 to an intronic motif. Here, the authors show that ASAP and PRC1, two interacting partner complexes of VAL1, mediate co-transcriptional repression and chromatin modulation to effectively co-ordinate different steps in FLC silencing.
- Pawel Mikulski
- , Philip Wolff
- & Caroline Dean
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Article
| Open AccessPRC1-mediated epigenetic programming is required to generate the ovarian reserve
In humans, the ovarian reserve is maintained over decades by meiotic arrest of oocytes. Here the authors show that Polycomb Repressive Complex 1 (PRC1)-mediated epigenetic programming is essential for formation of ovarian reserve and thus female reproductive lifespan.
- Mengwen Hu
- , Yu-Han Yeh
- & Satoshi H. Namekawa
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Article
| Open AccessRegulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity
Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.
- Reuben Franklin
- , Yiming Guo
- & Sihem Cheloufi
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Article
| Open AccessDNA sequence-dependent formation of heterochromatin nanodomains
The ability to predict epigenetic regulation is an important challenge in biology. Here the authors describe heterochromatin nanodomains (HNDs) and compare four different types of H3K9me2/3-marked HNDs in mouse embryonic stem cells. They further develop a computational framework to predict genome-wide HND maps from DNA sequence and protein concentrations, at single-nucleotide resolution.
- Graeme J. Thorn
- , Christopher T. Clarkson
- & Vladimir B. Teif
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| Open AccessBAF complex-mediated chromatin relaxation is required for establishment of X chromosome inactivation
Female embryonic stem cells (ESCs) are the ideal model to study X chromosome inactivation (XCI) establishment; however, these cells are challenging to keep in culture. Here the authors create fluorescent ‘Xmas’ reporter mice as a renewable source of ESCs and show nucleosome remodelers Smarcc1 and Smarca4 create a nucleosome-free promoter region prior to the establishment of silencing.
- Andrew Keniry
- , Natasha Jansz
- & Marnie E. Blewitt
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Article
| Open AccessTASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV
The human silencing hub (HUSH) complex, which includes TASOR, deposits repressive marks on HIV proviruses, resulting in gene repression. Here, Matkovic et al. show that TASOR interacts with RNA Polymerase II, predominantly under its elongating state, and RNA degradation proteins to repress HIV provirus expression.
- Roy Matkovic
- , Marina Morel
- & Florence Margottin-Goguet
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Article
| Open AccessProtein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response
Microsatellite instability (MSI), caused by deficiency of the DNA mismatch repair system, has been associated with improved response to immune checkpoint blockade (ICB). Here the authors show that inactivation of protein phosphatase 2A induces a MSI status, promoting cytotoxic T cell infiltration and response to ICB in pre-clinical cancer models.
- Yu-Ting Yen
- , May Chien
- & Shih-Chieh Hung
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Article
| Open AccessSpatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis
How enhancers transition from a hypoacetylated primed state to a hyperacetylated-active state in response to differentiation stimuli is incompletely understood. Here the authors show that SETD5 forms a complex with NCoR-HDAC3 co-repressor to prevent histone acetylation of master adipogenic gene enhancers, while SETD5 degradation triggers enhancer hyperacetylation and transition to active state.
- Yoshihiro Matsumura
- , Ryo Ito
- & Juro Sakai
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| Open AccessRepression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing
Germline genes are repressed by DNA methylation and histone marks. Here, the authors show that specific germline genes hypomethylated pre-implantation are enriched for PRC1.6, H2AK119ub1 and H3K9me3, which coordinately repress their expression.
- Kentaro Mochizuki
- , Jafar Sharif
- & Matthew C. Lorincz
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| Open AccessLoss of PRC2 subunits primes lineage choice during exit of pluripotency
Polycomb Repressive Complex 2, an important regulator of embryonic development, exists in two configurations, PRC2.1 and PRC2.2. Here the authors dissect the functional contributions of these two PRC2 subunits and observed complex-specific alterations in the cell state of pluripotent and early differentiating cells.
- Chet H. Loh
- , Siebe van Genesen
- & Gert Jan C. Veenstra
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Article
| Open AccessMammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males
The mammalian SWI/SNF nucleosome remodeler is required for spermatogenesis. Here, the authors show that PBAF is essential for meiotic cell division in males and required to activate the expression of critical genes involved in spindle assembly and nuclear division in spermatocytes.
- Debashish U. Menon
- , Oleksandr Kirsanov
- & Terry Magnuson
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Article
| Open AccessIntrons control stochastic allele expression bias
Stochastic autosomal allele expression bias has been widely documented, yet the mechanisms behind this consequential phenomenon remain poorly understood. Here the authors show that the presence of introns greatly restricts monoallelic expression in a C. elegans model.
- Bryan Sands
- , Soo Yun
- & Alexander R. Mendenhall
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| 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 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 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 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 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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| 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 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 AccessMetabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation
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
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Article
| Open AccessNanobody-mediated control of gene expression and epigenetic memory
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
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Article
| Open AccessPrimary effusion lymphoma enhancer connectome links super-enhancers to dependency factors
Primary effusion lymphoma (PEL) has a very poor prognosis. Here, the authors perform H3K27ac HiChIP in PEL cells and generate the PEL enhancer connectome, linking enhancers and promoters in PEL, as well as super-enhancers to dependency factors.
- Chong Wang
- , Luyao Zhang
- & Bo Zhao
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Article
| Open AccessCoupling of H3K27me3 recognition with transcriptional repression through the BAH-PHD-CPL2 complex in Arabidopsis
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
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Article
| Open AccessThe HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
The HUSH complex has been implicated in repressing LINE-1 elements. Here the authors reveal that the complex negatively regulates the type I IFN response in human cells through epigenetic regulation of LINE-1 elements
- Hale Tunbak
- , Rocio Enriquez-Gasca
- & Helen M. Rowe
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Article
| Open AccessBroad genic repression domains signify enhanced silencing of oncogenes
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
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Article
| Open AccessTASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control
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
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Article
| Open AccessDEPS-1 is required for piRNA-dependent silencing and PIWI condensate organisation in Caenorhabditis elegans
The C. elegans PIWI protein PRG-1 resides in the membraneless organelle P granule. Here, the authors identify the constitutive P granule protein DEPS-1 as an interactor of PRG-1 and show its function in piRNA-dependent silencing. DEPS-1 and PRG-1 form elongated condensates in vivo.
- Kin Man Suen
- , Fabian Braukmann
- & Eric Alexander Miska
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Article
| Open AccessThe characterization of Mediator 12 and 13 as conditional positive gene regulators in Arabidopsis
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
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Article
| Open AccessConserved protein Pir2ARS2 mediates gene repression through cryptic introns in lncRNAs
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
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Article
| Open AccessDisruption of ATRX-RNA interactions uncovers roles in ATRX localization and PRC2 function
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
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Article
| Open AccessHeat stress-induced transposon activation correlates with 3D chromatin organization rearrangement in Arabidopsis
Heat stress can activate heterochromatin-associated transposon elements (TEs). Here, the authors show that heat stress leads to global rearrangement of 3D genome and TEs activation closely correlates with 3D chromatin organization rearrangement in Arabidopsis.
- Linhua Sun
- , Yuqing Jing
- & Weiqiang Qian
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Article
| Open AccessRNA-DNA strand exchange by the Drosophila Polycomb complex PRC2
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
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Article
| Open AccessParallel evolution of dominant pistil-side self-incompatibility suppressors in Arabidopsis
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
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Article
| Open AccessTransposon age and non-CG methylation
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