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Deciphering inhibitory activities towards deposition of epigenetic marks controlling ageing rate


Project 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.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

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).

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