Parental contribution of modified RNAs

AKAY_U21DTP2

Germline stem cells are essential for the survival of organisms by giving rise to the offspring. Gene expression changes within the germ cells can affect embryonic development and in some organisms such changes are transgenerationally inherited. RNA is at the centre of many gene regulatory processes. There are currently more than 150 diverse chemical modifications found on RNA and a greater number of proteins are required for their synthesis and recognition. Recent discoveries have shown that RNA modifications can be dynamically regulated and they have been implicated in embryonic development, longevity, neurological diseases and cancers in humans and in animal models.

How do RNA modifications regulate gene expression in the germ cells? Our RNA (epi)genetics laboratory addresses this broad question using the nematode Caenorhabditis elegans as an animal model.

The PhD project aims to understand how RNA modification mediated gene expression changes affect early embryonic development. The maternal (oocytes) and paternal (sperm) contribution of gene regulation can directly affect early embryonic development. In C. elegans such intergenerational gene expression changes can further lead to transgenerational phenotypes. RNA modifications are known to control the stability and dynamics of RNA deposited on oocytes and sperm which in turn could contribute to embryonic developmental and transgenerational phenotypes. The project will combine powerful C. elegans genetics with CRISPR/Cas9 mutagenesis, RNA sequencing and microscopy. This project will lead to novel discoveries in a new area of biology that will influence research in multiple areas (germ cell biology, embryonic development and inter/transgenerational phenotypes).

We offer a multidisciplinary and supportive environment. The student will have a wide range of support to learn different techniques and will interact with national and international laboratories working on RNA modifications. The student will attend conferences, seminars and our annual laboratory retreat. The student will be given internal and external mentorship and career development support. Our new RNA (epi)genetics laboratory is funded by a prestigious UK Research and Innovation funding and provides generous resources and instruments.

References:

I. A. Roundtree, M. E. Evans, T. Pan, C. He, Dynamic RNA Modifications in Gene Expression Regulation. Cell. 169, 1187–1200 (2017).

A. Akay et al., The Helicase Aquarius/EMB-4 Is Required to Overcome Intronic Barriers to Allow Nuclear RNAi Pathways to Heritably Silence Transcription. Dev. Cell. 42, 241–255.e6 (2017).

P. van Delft et al., The Profile and Dynamics of RNA Modifications in Animals. Chembiochem. 18, 979–984 (2017).