C. elegans Heterochromatin Factor SET-32 Plays an Essential Role in Transgenerational Establishment of Nuclear RNAi-Mediated Epigenetic Silencing

Natallia Kalinava, Julie Zhouli Ni, Zoran Gajic, Matthew Kim, Helen Ushakov, Sam Guoping Gu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The dynamic process by which nuclear RNAi engages a transcriptionally active target, before the repressive state is stably established, remains largely a mystery. Here, we found that the onset of exogenous dsRNA-induced nuclear RNAi in C. elegans is a transgenerational process, and it requires a putative histone methyltransferase (HMT), SET-32. By developing a CRISPR-based genetic approach, we found that silencing establishment at the endogenous targets of germline nuclear RNAi also requires SET-32. Although SET-32 and two H3K9 HMTs, MET-2 and SET-25, are dispensable for the maintenance of silencing, they do contribute to transcriptional repression in mutants that lack the germline nuclear Argonaute protein HRDE-1, suggesting a conditional role of heterochromatin in the maintenance phase. Our study indicates that (1) establishment and maintenance of siRNA-guided transcriptional repression are two distinct processes with different genetic requirements and (2) the rate-limiting step of the establishment phase is a transgenerational, chromatin-based process. Deciphering mechanisms of transgenerational epigenetic gene regulation is critical for understanding of development, aging, and disease. In this study, Kalinava et al. examine the establishment of RNAi-mediated epigenetic silencing. The identification of the bottleneck step provides critical insight into the regulation of this pathway.

Original languageEnglish (US)
Pages (from-to)2273-2284.e3
JournalCell Reports
Volume25
Issue number8
DOIs
StatePublished - Nov 20 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • CRISPR
  • HRDE-1
  • MET-2
  • SET-25
  • SET-32
  • epigenetic silencing
  • heterochromatin
  • nuclear RNAi
  • silencing establishment
  • transgenerational epigenetic inheritance

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