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Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing.

ABSTRACT: An animal that can transfer gene-regulatory information from somatic cells to germ cells may be able to communicate changes in the soma from one generation to the next. In the worm Caenorhabditis elegans, expression of double-stranded RNA (dsRNA) in neurons can result in the export of dsRNA-derived mobile RNAs to other distant cells. Here, we show that neuronal mobile RNAs can cause transgenerational silencing of a gene of matching sequence in germ cells. Consistent with neuronal mobile RNAs being forms of dsRNA, silencing of target genes that are expressed either in somatic cells or in the germline requires the dsRNA-selective importer SID-1. In contrast to silencing in somatic cells, which requires dsRNA expression in each generation, silencing in the germline is heritable after a single generation of exposure to neuronal mobile RNAs. Although initiation of inherited silencing within the germline requires SID-1, a primary Argonaute RDE-1, a secondary Argonaute HRDE-1, and an RNase D homolog MUT-7, maintenance of inherited silencing is independent of SID-1 and RDE-1, but requires HRDE-1 and MUT-7. Inherited silencing can persist for >25 generations in the absence of the ancestral source of neuronal dsRNA. Therefore, our results suggest that sequence-specific regulatory information in the form of dsRNA can be transferred from neurons to the germline to cause transgenerational silencing.

SUBMITTER: Devanapally S

PROVIDER: S-EPMC4343102 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing.

Devanapally Sindhuja S Ravikumar Snusha S Jose Antony M AM

Proceedings of the National Academy of Sciences of the United States of America 20150202 7

An animal that can transfer gene-regulatory information from somatic cells to germ cells may be able to communicate changes in the soma from one generation to the next. In the worm Caenorhabditis elegans, expression of double-stranded RNA (dsRNA) in neurons can result in the export of dsRNA-derived mobile RNAs to other distant cells. Here, we show that neuronal mobile RNAs can cause transgenerational silencing of a gene of matching sequence in germ cells. Consistent with neuronal mobile RNAs bei ...[more]

PMID: 25646479

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Project description:ABSTRACT Aims: Double-stranded breaks (DSBs) cause genomic instability, a hallmark of aging, and activate the DNA damage response (DDR) and the cytosolic DNA-sensing proteins (CDSP) pathways. The activated pathways induce cell cycle arrest, inflammation, senescence, cell death, fibrosis, and organ dysfunction. The purpose of the study was to identify and characterize genome-wide DSBs at the nucleotide resolution in adult cardiac myocytes. Methods and Results: We identified the genome-wide DSBs in the genomes of ~ 6 million adult cardiac myocytes (1 million per sample) in the 3 wild-type and 3 myocyte-specific LMNA-deficient mice (Myh6-Cre:LmnaF/F) mice by END-Sequencing. We identified 6,774 differential DSBs between the wild-type and Myh6-Cre:LmnaF/F cardiac myocytes, which, except for 8, were exclusive to the Myh6-Cre:LmnaF/F genotype. The differential DSBs were enriched in the gene regions, transcription initiation sites, cardiac transcription factor motifs, and at the G quadruplex forming structures, suggesting the involvement of the transcriptional stress. Because LMNA regulates transcription, we performed a CUT&RUN assay with an anti-LMNA antibody (N=5) to test the role of transcriptional stress in an increased prevalence of DSBs. We identified an average of 818 genome-wide lamin-associated domains (LADs), which encompassed 30% of the mouse genome. LADs were associated with a 16-fold reduction in the transcript levels of protein-coding genes located at the LAD regions (N=3,975) as opposed to genes located at the non-LAD regions (N=~ 17,778). Consistent with increased transcription at the non-LAD regions DSBs were ~ 6-fold more prevalent in the non-LAD than LAD regions. Likewise, the loss of LAD was associated with a 2.3-fold higher prevalence of differential DSBs in the Myh6-Cre:LmnaF/F cardiac myocyte genomes, which were predominantly localized to the transcription start sites. Conclusions: To our knowledge, this is the first identification of the DSBs, a hallmark of aging, at the nucleotide resolution in the cardiovascular system. The findings implicate transcriptional stress in the pathogenesis of DSB and the protective role of LMNA against DSBs likely through transcriptional suppression. Given the ubiquitous nature of transcriptional stress, DSBs are expected to be pervasive and pathogenic through activation of the DDR and CDSP pathways not only in cardiovascular diseases but also in other conditions, including aging.

Dataset Information

Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing.

Publications

Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing.

Similar Datasets

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