Loss of dna methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling

Yelena Chernyavskaya, Raksha Mudbhary, Chi Zhang, Debra Tokarz, Vinitha Jacob, Smita Gopinath, Xiaochen Sun, Shuang Wang, Elena Magnani, Bhavani P. Madakashira, Jeffrey A. Yoder, Yujin Hoshida, Kirsten Sadler Edepli

Research output: Contribution to journalArticle

Abstract

Complex cytoplasmic nucleotide-sensing mechanisms can recognize foreign DNA based on a lack of methylation and initiate an immune response to clear the infection. Zebrafish embryos with global DNA hypomethylation caused by mutations in the ubiquitin-like with PHD and ring finger domains 1 (uhrf1) or DNA methyltransferase 1 (dnmt1) genes exhibit a robust interferon induction characteristic of the first line of defense against viral infection. We found that this interferon induction occurred in non-immune cells and examined whether intracellular viral sensing pathways in these cells were the trigger. RNA-seq analysis of uhrf1 and dnmt1 mutants revealed widespread induction of Class I retrotransposons and activation of cytoplasmic DNA viral sensors. Attenuating Sting, phosphorylated Tbk1 and, importantly, blocking reverse transcriptase activity suppressed the expression of interferon genes in uhrf1 mutants. Thus, activation of transposons in cells with global DNA hypomethylation mimics a viral infection by activating cytoplasmic DNA sensors. This suggests that antiviral pathways serve as surveillance of cells that have derepressed intragenomic parasites due to DNA hypomethylation.

Original languageEnglish (US)
Pages (from-to)2925-2939
Number of pages15
JournalDevelopment (Cambridge)
Volume144
Issue number16
DOIs
StatePublished - Aug 15 2017

Fingerprint

Retroelements
Zebrafish
Methylation
Antiviral Agents
Embryonic Structures
DNA
Interferons
Methyltransferases
Virus Diseases
RNA-Directed DNA Polymerase
Viral DNA
Bites and Stings
Ubiquitin
Fingers
Parasites
Nucleotides
RNA
Gene Expression
Mutation
Infection

Keywords

  • Antiviral
  • DNA methylation
  • Interferon
  • Transposon
  • Uhrf1

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Loss of dna methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling. / Chernyavskaya, Yelena; Mudbhary, Raksha; Zhang, Chi; Tokarz, Debra; Jacob, Vinitha; Gopinath, Smita; Sun, Xiaochen; Wang, Shuang; Magnani, Elena; Madakashira, Bhavani P.; Yoder, Jeffrey A.; Hoshida, Yujin; Sadler Edepli, Kirsten.

In: Development (Cambridge), Vol. 144, No. 16, 15.08.2017, p. 2925-2939.

Research output: Contribution to journalArticle

Chernyavskaya, Y, Mudbhary, R, Zhang, C, Tokarz, D, Jacob, V, Gopinath, S, Sun, X, Wang, S, Magnani, E, Madakashira, BP, Yoder, JA, Hoshida, Y & Sadler Edepli, K 2017, 'Loss of dna methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling', Development (Cambridge), vol. 144, no. 16, pp. 2925-2939. https://doi.org/10.1242/dev.147629
Chernyavskaya Y, Mudbhary R, Zhang C, Tokarz D, Jacob V, Gopinath S et al. Loss of dna methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling. Development (Cambridge). 2017 Aug 15;144(16):2925-2939. https://doi.org/10.1242/dev.147629
Chernyavskaya, Yelena ; Mudbhary, Raksha ; Zhang, Chi ; Tokarz, Debra ; Jacob, Vinitha ; Gopinath, Smita ; Sun, Xiaochen ; Wang, Shuang ; Magnani, Elena ; Madakashira, Bhavani P. ; Yoder, Jeffrey A. ; Hoshida, Yujin ; Sadler Edepli, Kirsten. / Loss of dna methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling. In: Development (Cambridge). 2017 ; Vol. 144, No. 16. pp. 2925-2939.
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