Cryptic genetic variation of expression quantitative trait locus architecture revealed by genetic perturbation in Caenorhabditis elegans.

Genetic perturbation in different genetic backgrounds can cause a range of phenotypes within a species. These phenotypic differences can be the result of the interaction between the genetic background and the perturbation. Previously, we reported that perturbation of gld-1, an important player in the developmental control of Caenorhabditis elegans, released cryptic genetic variation (CGV) affecting fitness in different genetic backgrounds.

The mTOR-S6 kinase pathway promotes stress granule assembly.

Stress granules are cytoplasmic mRNA-protein complexes that form upon the inhibition of translation initiation and promote cell survival in response to environmental insults. However, they are often associated with pathologies, including neurodegeneration and cancer, and changes in their dynamics are implicated in ageing. Here we show that the mTOR effector kinases S6 kinase 1 (S6K1) and S6 kinase 2 (S6K2) localise to stress granules in human cells and are required for their assembly and maintenance after mild oxidative stress.

A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity.

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity.

An RNAi-based dimorphic genetic screen identified the double bromodomain protein BET-1 as a sumo-dependent attenuator of RAS-mediated signalling.

Attenuation of RAS/RAF/MAPK signalling is essential to prevent hyperactivation of this oncogenic pathway. In C. elegans, the sumoylation pathway and a combination of histone tail modifications regulate gene expression to attenuate the LET-60 (RAS) signalling pathway.

Maintenance of muscle myosin levels in adult C. elegans requires both the double bromodomain protein BET-1 and sumoylation.

Attenuation of RAS-mediated signalling is a conserved process essential to control cell proliferation, differentiation, and apoptosis. Cooperative interactions between histone modifications such as acetylation, methylation and sumoylation are crucial for proper attenuation in C. elegans, implying that the proteins recognising these histone modifications could also play an important role in attenuation of RAS-mediated signalling.

Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages.

A fitness assay for comparing RNAi effects across multiple C. elegans genotypes.

Background: RNAi technology by feeding of E. coli containing dsRNA in C. elegans has significantly contributed to further our understanding of many different fields, including genetics, molecular biology, developmental biology and functional genomics.

Lineage specific trimethylation of H3 on lysine 4 during C. elegans early embryogenesis.

In many organisms early embryogenesis is characterised by a period refractory to transcription. In Caenorhabditis elegans, the one-cell embryo is transcriptionally inactive, but at around eight-cell stage transcription is activated in the somatic lineage. This model suggests that histone tail modifications associated with activation of transcription, such as di- or trimethylation of histone 3 on lysine 4 (H3K4me2/me3) should be enriched in the somatic lineage.

The Caenorhabditis elegans CDT-2 ubiquitin ligase is required for attenuation of EGFR signalling in vulva precursor cells.

Background: Attenuation of the EGFR (Epidermal Growth Factor Receptor) signalling cascade is crucial to control cell fate during development. A candidate-based RNAi approach in C. elegans identified CDT-2 as an attenuator of LET-23 (EGFR) signalling.

Methylation and demethylation activities of a C. elegans MLL-like complex attenuate RAS signalling.

The conserved Mixed Lineage Leukaemia (MLL) complex deposits activating methyl marks on histone tails through a methyltransferase (MT) activity. Here we provide in vivo evidence that in addition to methylation, the C. elegans MLL-like complex can remove specific methyl marks linked to repression of transcription.