CSR-1 RNAi pathway positively regulates histone expression in C. elegans

EMBO J. 2012 Oct 3;31(19):3821-32. doi: 10.1038/emboj.2012.216. Epub 2012 Aug 3.

Abstract

Endogenous small interfering RNAs (endo-siRNAs) have been discovered in many organisms, including mammals. In C. elegans, depletion of germline-enriched endo-siRNAs found in complex with the CSR-1 Argonaute protein causes sterility and defects in chromosome segregation in early embryos. We discovered that knockdown of either csr-1, the RNA-dependent RNA polymerase (RdRP) ego-1, or the dicer-related helicase drh-3, leads to defects in histone mRNA processing, resulting in severe depletion of core histone proteins. The maturation of replication-dependent histone mRNAs, unlike that of other mRNAs, requires processing of their 3'UTRs through an endonucleolytic cleavage guided by the U7 snRNA, which is lacking in C. elegans. We found that CSR-1-bound antisense endo-siRNAs match histone mRNAs and mRNA precursors. Consistently, we demonstrate that CSR-1 directly binds to histone mRNA in an ego-1-dependent manner using biotinylated 2'-O-methyl RNA oligonucleotides. Moreover, we demonstrate that increasing the dosage of histone genes rescues the lethality associated with depletion of CSR-1 and EGO-1. These results support a positive and direct effect of RNAi on histone gene expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Gene Dosage
  • Gene Silencing
  • Histones / biosynthesis*
  • Protein Binding
  • RNA Interference / physiology*
  • RNA Replicase / genetics
  • RNA Replicase / metabolism
  • RNA, Messenger / chemistry

Substances

  • CSR-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Histones
  • RNA, Messenger
  • Drh-3 protein, C elegans
  • EGO-1 protein, C elegans
  • RNA Replicase
  • DEAD-box RNA Helicases