The meiotic phosphatase GSP-2/PP1 promotes germline immortality and small RNA-mediated genome silencing

Abstract

Germ cell immortality, or transgenerational maintenance of the germ line, could be promoted by mechanisms that could occur in either mitotic or meiotic germ cells. Here we report for the first time that the GSP-2 PP1/Glc7 phosphatase promotes germ cell immortality. Small RNA-induced genome silencing is known to promote germ cell immortality, and we identified a separation-of-function allele of C . elegans gsp-2 that is compromised for germ cell immortality and is also defective for small RNA-induced genome silencing and meiotic but not mitotic chromosome segregation. Previous work has shown that GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. At the generation of sterility, gsp-2 and lab-1 mutant adults displayed germline degeneration, univalents, histone methylation and histone phosphorylation defects in oocytes, phenotypes that mirror those observed in sterile small RNA-mediated genome silencing mutants. Our data suggest that a meiosis-specific function of GSP-2 ties small RNA-mediated silencing of the epigenome to germ cell immortality. We also show that transgenerational epigenomic silencing at hemizygous genetic elements requires the GSP-2 phosphatase, suggesting a functional link to small RNAs. Given that LAB-1 localizes to the interface between homologous chromosomes during pachytene, we hypothesize that small localized discontinuities at this interface could promote genomic silencing in a manner that depends on small RNAs and the GSP-2 phosphatase.

Germ granule dysfunction is a hallmark and mirror of Piwi mutant sterility

“…pathway mutants 9,21 . P granule proteins PGL-1 and PGL-3 have been shown to vanish in wild-type germ cells that undergo apoptosis 39,40 .…”

“…Telomerase is suppressed in somatic cells of humans and other large mammals, which results in telomere erosion. This serves as a "biological clock" that suppresses tumor formation but promotes aging by triggering a form of permanent cell cycle arrest termed senescence [7][8][9][10][11][12] . Somatic cells of short-lived mice possess telomerase, but accumulate other forms of stress that increase transcription at the p16 Ink4a locus, which can induce senescence independently of shortened telomeres.…”

“…We therefore reasoned that C. elegans mortal germline mutants that are not defective for telomerase could uncover additional pathways or factors that regulate cellular senescence and aging. In this regard, deficiency for the C. elegans Argonaute protein Piwi/PRG-1 and related proteins that promote small RNA-mediated genome silencing compromises germ cell immortality [8][9][10][11] but does not result in creation of end-to-end chromosome fusions that are a hallmark of late-generation C. elegans telomerase mutants 4,5 .…”

“…Deficiency for the C. elegans Piwi ortholog prg-1 does not induce the immediate sterility phenotype observed in Piwi mutants from other species, but instead compromises germ cell immortality 8 . The delayed sterility of late-generation C. elegans Piwi pathway mutants 8,9,11 could result from gradual decay of Piwi/piRNA-dependent histone silencing marks as germ cells proliferate over several generations. Heterochromatin dysfunction in C. elegans has been associated with increased levels of transposon and tandem repeat expression, with RNA-DNA hybrid formation, and with transposon-induced DNA damage [18][19][20] .…”

Accurate determination of node and arc multiplicities in de bruijn graphs using conditional random fields

“…size Accession no. Model Read length Reference S. enterica NC_011083.1 5.1 Mb SRR1206093 MiSeq 2×250 bp [ 30 ] P. aeruginosa NC_002516.2 6.3 Mb ERR330008 MiSeq 2×150 bp [ 31 ] C. elegans WBcel235 100.3 Mb SRR5865874 HiSeq 2000 2×100 bp [ 32 ] A. thaliana TAIR10.1 119.4 Mb ERR1913320 NextSeq 500 2×150 bp - H. sapiens GRCh38 3099.8 Mb ERR194147 HiSeq 2000 2×100 bp [ 33 ] …”