Pharyngeal pumping rate does not reflect lifespan extension in C. elegans transgenerational longevity mutants.

Epigenetic modifications must be reprogrammed with each new generation. In Caenorhabditis elegans , defects in histone methylation reprogramming allow for the transgenerational acquisition of longevity. For example, mutations in the putative H3K9 demethylase JHDM-1 extend lifespan after six to ten generations. We noticed that long-lived jhdm-1 mutants appear healthier than wild-type animals from the same generation. To quantify health, we compared the common metric of pharyngeal pumping rate at specific adult ages between early-gen populations with normal lifespans and late-gen populations with long lifespans. Longevity did not affect pumping rate, but long-lived mutants stop pumping at a younger age, suggesting a possible conservation of energy to extend lifespan.

Repressive H3K9me2 protects lifespan against the transgenerational burden of COMPASS activity in C. elegans.

In Caenorhabditis elegans, mutations in WDR-5 and other components of the COMPASS H3K4 methyltransferase complex extend lifespan and enable its inheritance. Here, we show that wdr-5 mutant longevity is itself a transgenerational trait that corresponds with a global enrichment of the heterochromatin factor H3K9me2 over twenty generations. In addition, we find that the transgenerational aspects of wdr-5 mutant longevity require the H3K9me2 methyltransferase MET-2, and can be recapitulated by removal of the putative H3K9me2 demethylase JHDM-1. Finally, we show that the transgenerational acquisition of longevity in jhdm-1 mutants is associated with accumulating genomic H3K9me2 that is inherited by their long-lived wild-type descendants at a subset of loci. These results suggest that heterochromatin facilitates the transgenerational establishment and inheritance of a complex trait. Based on these results, we propose that transcription-coupled H3K4me via COMPASS limits lifespan by encroaching upon domains of heterochromatin in the genome.

End joining at Caenorhabditis elegans telomeres.

Critically shortened telomeres can be subjected to DNA repair events that generate end-to-end chromosome fusions. The resulting dicentric chromosomes can enter breakage-fusion-bridge cycles, thereby impeding elucidation of the structures of the initial fusion events and a mechanistic understanding of their genesis. Current models for the molecular basis of fusion of critically shortened, uncapped telomeres rely on PCR assays that typically capture fusion breakpoints created by direct ligation of chromosome ends. Here we use independent approaches that rely on distinctive features of Caenorhabditis elegans to study the frequency of direct end-to-end chromosome fusion in telomerase mutants: (1) holocentric chromosomes that allow for genetic isolation of stable end-to-end fusions and (2) unique subtelomeric sequences that allow for thorough PCR analysis of samples of genomic DNA harboring multiple end-to-end fusions. Surprisingly, only a minority of end-to-end fusion events resulted from direct end joining with no additional genome rearrangements. We also demonstrate that deficiency for the C. elegans Ku DNA repair heterodimer does not affect telomere length or cause synthetic effects in the absence of telomerase.