A Role for Caenorhabditis elegans COMPASS in Germline Chromatin Organization

Abstract

Deposition of histone H3 lysine 4 (H3K4) methylation at promoters is catalyzed by the SET1/COMPASS complex and is associated with context-dependent effects on gene expression and local changes in chromatin organization. The role of SET1/COMPASS in shaping chromosome architecture has not been investigated. Here we used Caenorhabditis elegans to address this question through a live imaging approach and genetic analysis. Using quantitative FRET (Förster resonance energy transfer)-based fluorescence lifetime imaging microscopy (FLIM) on germ cells expressing histones eGFP-H2B and mCherry-H2B, we find that SET1/COMPASS influences meiotic chromosome organization, with marked effects on the close proximity between nucleosomes. We further show that inactivation of set-2, encoding the C. elegans SET1 homologue, or CFP-1, encoding the chromatin targeting subunit of COMPASS, enhances germline chromosome organization defects and sterility of condensin-II depleted animals. set-2 loss also aggravates germline defects resulting from conditional inactivation of topoisomerase II, another structural component of chromosomes. Expression profiling of set-2 mutant germlines revealed only minor transcriptional changes, suggesting that the observed effects are at least partly independent of transcription. Altogether, our results are consistent with a role for SET1/COMPASS in shaping meiotic chromosomes in C. elegans, together with the non-histone proteins condensin-II and topoisomerase. Given the high degree of conservation, our findings expand the range of functions attributed to COMPASS and suggest a broader role in genome organization in different species.

Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans

“…Although set-2(syb2085) and set-2(bn129) mutants became rapidly sterile at 25°C, set-2(ok952) mutant animals remained fertile, consistent with only a modest loss of H3K4me2/3 in these animals. Sterility in mutants lacking SET-2 catalytic activity may be related to altered chromatin organization or global deregulation of the germline transcriptional program, as we previously observed in the set-2(bn129) mutants (67,68). Interestingly, a similar correlation was not observed between H3K4 methylation and the longevity phenotype, in that all three set-2 mutants showed a reduction in lifespan despite having markedly different global H3K4me2/3 levels.…”

Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans

“…Although set-2(syb2085) and set-2(bn129) mutants were sterile, set-2(ok952) mutant animals were fertile, consistent with only a modest loss of H3K4me2/3 in these animals. Sterility in mutants lacking SET-2 catalytic activity may be related to altered chromatin organization or global deregulation of the germline transcriptional program, as we previously observed in the set-2(bn129) mutants (56,57). Interestingly, a similar correlation was not observed between H3K4 methylation and the longevity phenotype, in that all three set-2 mutants showed a reduction in lifespan despite having markedly different global H3K4 methylation levels.…”

The zinc-finger protein OEF-1 stabilizes histone modification patterns and promotes efficient splicing in the Caenorhabditis elegans germline

“…Using the RNA-seq data from dissected wild type and oef-1 mutant gonads, we analyzed the frequency of intron retention, which indicates a disruption of normal splicing events. To rigorously define the baseline variation of intron retention that might normally occur between any two independent samples, we established a control comparison between our wild-type sample and an independently collected wild-type dataset, also from dissected gonads ( Herbette et al 2020 ) (Supplementary Figure S10). We then determined the rate of intron retention between oef-1 and our wild-type sample and found that loss of OEF-1 activity led to significantly increased intron retention compared to this control ( Figure 6A ).…”

“… oef-1 mutants exhibit decreased splicing integrity. (A) Cumulative plot showing an increase in intron retention in oef-1 vs wild type (labeled oef-1 /wt) relative to wild type vs an independent wild type sample ( Herbette et al 2020 ; labeled control, ctl). Differential intron retention [IR, absolute log2 fold change (FC)] is on the x -axis, and accumulated incidence (cumulative frequency) on the y -axis for the oef-1 /wt (red) and control (black) comparisons.…”