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Poulin Lab

Positions

Deciphering inhibitory activities towards deposition of epigenetic marks controlling ageing rate

Funding: Project available for individuals with self arranged funding.

Description

Over two decades of intense research in the field of epigenetics have produced compelling evidence that chromatin modifications are crucial for processes such as DNA repair, transcription, splicing, mitosis, meiosis, and in the preservation of the epigenetic memory of cells. One of the best examples of a chromatin modification implicated in that sort of repertoire of functions is methylation at histone 3 on lysine 4 (H3K4).

 

This abundant and conserved modification is deposited through a complex called the MLL/SET/COMPASS complex comprising a core complex and Histone MethylTransferase (HMTs) enzymes. Interestingly, lowering the levels of methyl marks at H3K4 using RNAi directed at the core complex increases C. elegans lifespan.

 

We have recently investigated how the core complex contributes towards the deposition of methyl marks at H3K4 and unexpectedly revealed an inhibitory activity towards deposition. The core complex component responsible for this inhibitory activity is RBBP-5.

 

Your project will aim at characterising this novel activity using RNAi, genetics, and next generation sequencing technologies such as RNA-seq, ChIP-seq, and GRO-seq. At the end of your PhD, you will have developed an expertise of both wet lab and bio-informatics, which are used across disciplines and are in demand.

 

Related Publications

  • Wang, S., Fisher, K. & Poulin, G. B. Lineage specific trimethylation of H3 on lysine 4 during C. elegans early embryogenesis. Dev Biol 355, 227–238 (2011).

 

  • Fisher, K., Southall, S. M., Wilson, J. R. & Poulin, G. B. Methylation and demethylation activities of a C. elegans MLL-like complex attenuate RAS signalling. Dev Biol 341, 142–153 (2010).

 

  • Greer, E. L. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature (2010).

 

  • Han, S. & Brunet, A. Histone methylation makes its mark on longevity. Trends Cell Biol 22, 42–49 (2012).

 

  • Shilatifard, A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 81, 65–95 (2012).

 

Regulation of stress-responses and ageing

Funding: Project available for individuals with self arranged funding.

Description

Ageing occurs by the accumulation of damage to cells leading to progressive deterioration of physiological functions. It is influenced by both genetic and environmental factors. Importantly, genetic manipulations that slow ageing can also delay the onset of many diseases such as cancer and those associated with neuronal and muscle degeneration. Therefore, targeting the molecular basis of ageing may also protect from ageing-related disease. The signalling pathways that regulate lifespan are often associated with the cellular response to stress or nutrients. Mitochondrial function is sensitive to both and mutations in a number of genes encoding mitochondrial proteins affect lifespan. Mitochondria are a major source of reactive oxygen species (ROS) that are by-products of the electron transport chain. ROS can cause damage to cells so it is important for mitochondria to communicate effectively with the nucleus to promote protective responses and maintain homeostasis. Our research has uncovered a novel route of communication between mitochondria and nuclei that is sensitive to ROS and regulates the transcription of stress-response genes in both the model organism C. elegans and in human cells. Furthermore, perturbation of this pathway modulates lifespan in both C. elegans and mice. Projects are available to investigate how this novel pathway regulates transcriptional responses and contributes to ageing and ageing-related diseases. Approaches used will include cell culture, C. elegans transgenics, recombinant protein expression, mutagenesis, qPCR, immunoblotting and immunoprecipitation, fluorescence microscopy, RNAi, CRISPR gene editing and genomics.

 

 

Related Publications

  • Kenyon, CJ (2010) Nature 464: 504-12.
  • Kourtis, N. and Tavernarkis, N. (2011) EMBO J. 30:2520-31.
  • Kotiadis, VN. et al., (2014) Biochim Biophys Acta 1840: 1254-65.