The Helicase Aquarius/EMB-4 Is Required to Overcome Intronic Barriers to Allow Nuclear RNAi Pathways to Heritably Silence Transcription

Akay, Alper; Domenico, Tomás Di; Suen, Kin Man; Nabih, Amena; Parada, Guillermo E.; Larance, Mark; Medhi, Ragini; Berkyurek, Ahmet C.; Zhang, Xinlian; Wedeles, Christopher J.; Rudolph, Konrad L. M.; Engelhardt, Jan; Hemberg, Martin; Ma, Ping; Lamond, Angus I.; Claycomb, Julie M.; Miska, Eric A.

doi:10.1016/j.devcel.2017.07.002

Cited by 67 publications

(58 citation statements)

References 109 publications

(152 reference statements)

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“…Downstream of mRNA scanning and siRNA generation, RNAi target genes are typically silenced by nuclear Argonaute proteins, HRDE-1 in the germline or NRDE-3 in the soma. HRDE-1 and its interactor EMB-4/Aquarius (27) (28) silence DEPS-1-regulated retrotransposons (Figure 4G, Supplemental Figure 4D). Loss of somatic nuclear Argonaute NRDE-3 and the viral RNA sensor DRH-1/RIG-I does not disrupt retrotransposon silencing (Supplemental Figure 4E).…”

Section: Resultsmentioning

confidence: 99%

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Fischer

Ruvkun

2019

Preprint

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18Endogenous retroviruses and LTR retrotransposons are mobile genetic elements that 19 are closely related to retroviruses. Desilenced endogenous retroviruses are associated 20 with human autoimmune disorders and neurodegenerative diseases. C. elegans and 21 related Caenorhabdites contain LTR retrotransposons and, as described here, 22 numerous integrated viral genes including viral envelope genes that are part of LTR 23 retrotransposons. We found that both LTR retrotransposons and endogenous viral 24 elements are silenced by ADARs (adenosine deaminases acting on double-stranded 25 RNA (dsRNA)) together with the endogenous RNAi factor ERI-6/7, a homolog of Mov10 26 helicase, a retrotransposon and retrovirus restriction factor in human. siRNAs 27 Transposons can have profound effects on cellular function such as disruption of gene 53 function by transposon insertion, cell death as a consequence of transposon-induced 54 double stranded breaks, and genomic rearrangements caused by homologous 55 recombination between repeat elements. Retrotransposons and endogenous 56 retroviruses may affect cellular function through overexpression of toxic proteins or the 57 activity of retroviral proteins on endogenous sequences. Palindromic repeat elements 58 such as those formed by adjacent but inverted insertion of vertebrate Alu elements 59 into genes can cause the accumulation of dsRNA. 60 Many RNA viruses replicate via a dsRNA intermediate, which is detected to 61 trigger an interferon-based antiviral response in mammals and an RNA interference 62 response in invertebrates. To avoid an anti-viral response to endogenous palindromic 63 dsRNAs when in fact there is no viral infection, ADARs edit adenosines to inosines in 64 endogenous dsRNA destabilizing the RNA duplex and thus preventing recognition by 65

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Section: Resultsmentioning

confidence: 99%

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Fischer

Ruvkun

2019

Preprint

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“…We speculate that nuclear RNA accumulation of the endogenous HRDE-1 targets may reflect aberrant structures or deficiencies in RNA-processing of these transcripts. Such connections have been found in S. pombe [41,42] and recently in C. elegans [43,44]. Investigating the cause of the nuclear enrichment will provide insights into the triggering mechanism of nuclear RNAi in C. elegans.…”

Section: Is Nuclear Accumulation a Sign Of "Foreign"?mentioning

confidence: 70%

The spatial and temporal dynamics of the nuclear RNAi-targeted RNA transcripts inCaenorhabditis elegans

Kalinava

Mendoza

et al. 2018

Preprint

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Small RNA-guided chromatin silencing, also referred to as nuclear RNAi, plays an essential role in genome surveillance in eukaryotes and provides a unique paradigm to explore the complexity in RNA-mediated chromatin regulation and transgenerational epigenetics. A well-recognized paradox in this research area is that transcription of the target loci is necessary for the initiation and maintenance of the silencing at the same loci. How the two opposing activities (transcriptional activation and repression) are coordinated during animal development is poorly understood. To resolve this gap, we took single-molecule RNA imaging, deep-sequencing, and genetic approaches towards delineating the developmental regulation and subcellular localization of RNA transcripts of two exemplary endogenous germline nuclear RNAi targets in C. elegans, Cer3 and Cer8 LTR retrotransposons.By examining the wild type and a collection of mutant strains, we found that transcription and silencing cycle of Cer3 and Cer8 is tightly coupled with the early embryogenesis and germline mitotic and meiotic cell cycles. Strikingly, Cer3 and Cer8 transcripts are exclusively localized in the nuclei of germ cells in both wild type and germline nuclear RNAi-defective mutant animals. RNA-sequencing analysis found that this nuclear enrichment feature is a general feature for the endogenous targets of the germline nuclear RNAi pathway. In addition, the germline and somatic repressions of Cer3 have different genetic requirement for the three H3K9 histone methyltransferases, MET-2, SET-25, and SET-32, in conjunction with the nuclear Argonaute protein WAGO-9/HRDE-1. These results provide a first comprehensive cellular and developmental characterization of the nuclear RNAi-targeted endogenous targets throughout animal reproductive cycle. Altogether, these results support a model in which (1) both the transcriptional activation and repression steps of the germline nuclear RNAi pathway are tightly coupled with animal development, (2) the endogenous targets exhibit a hallmark of nuclear enrichment of their transcripts, and (3) different heterochromatin enzymes play distinct roles in somatic and germline silencing of the endogenous targets.

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“…We conclude from the small RNAs characterisation of deps-1 mutants that deps-1 functions immediately downstream of prg-1 and upstream of, or in parallel to secondary endo-siRNA production. Of note, DEPS-1 was not found as an interactor of HRDE-1 (Akay et al, 2017), an essential Ago protein that transports 22Gs into the nucleus to initiate nuclear gene silencing further suggesting that DEPS-1 does not function downstream of secondary endo-siRNA biogenesis.…”

Section: Deps-1 Is Required For the Steady State Levels Of 22g Rnas Amentioning

confidence: 98%

Direct interaction of PIWI and DEPS-1 is essential for piRNA function and condensate ultrastructure inCaenorhabditis elegans

Braukmann

Butler

et al. 2019

Preprint

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Membraneless organelles are platforms for many aspects of RNA biology including small non-coding RNA (ncRNA) mediated gene silencing. How small ncRNAs utilise phase separated environments for their function is unclear. To address this question, we investigated how the PIWI-interacting RNA (piRNA) pathway engages with the membraneless organelle P granule in Caenorhabditis elegans. Proteomic analysis of the PIWI protein PRG-1 revealed an interaction with the constitutive P granule 2 protein DEPS-1. Furthermore we identified a novel motif on DEPS-1, PBS, which interacts directly with the Piwi domain of PRG-1. This protein complex forms intertwining ultrastructures to build elongated condensates in vivo. These suborganelle ultrastructures depend on the Piwi-interacting motif of DEPS-1 and mediate piRNA function. Additionally, we identify a novel interactor of DEPS-1, EDG-1, which is required for DEPS-1 condensates to form correctly. We show that DEPS-1 is not required for piRNA biogenesis but piRNA function: deps-1 mutants fail to produce the secondary endo-siRNAs required for the silencing of piRNA targets. Our study reveals how specific protein-protein interactions drive the spatial organisation and function of small RNA pathways within membraneless organelles.as the P-bodies and germ granules (Eulalio et al., 2007;Voronina et al., 2011).

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The Helicase Aquarius/EMB-4 Is Required to Overcome Intronic Barriers to Allow Nuclear RNAi Pathways to Heritably Silence Transcription

Cited by 67 publications

References 109 publications

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

The spatial and temporal dynamics of the nuclear RNAi-targeted RNA transcripts inCaenorhabditis elegans

Direct interaction of PIWI and DEPS-1 is essential for piRNA function and condensate ultrastructure inCaenorhabditis elegans

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