title: CSR-1 RNAi pathway positively regulates histone expression in C. elegans.
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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Avgousti
authors.forename: Santhosh
authors.initials: S
authors.lastname: Palani
authors.forename: Yekaterina
authors.initials: Y
authors.lastname: Sherman
authors.forename: Alla
authors.initials: A
authors.lastname: Grishok
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D020868:Gene Silencing; D006657:Histones / Q000096:biosynthesis*; D011485:Protein Binding; D034622:RNA Interference / Q000502:physiology*; D012333:RNA, Messenger / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism
chemical_list: C544459:CSR-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D006657:Histones; D012333:RNA, Messenger; C524398:Drh-3 protein, C elegans; C406772:EGO-1 protein, C elegans; D012324:RNA-Dependent RNA Polymerase; D053487:DEAD-box RNA Helicases