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Dissecting the molecular mechanisms of lncRNA function in X chromosome inactivation across mammalian gestation evolution

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  • Full or part time
    Dr J Aspden
    Dr N Forde
    Dr M. O'Connell
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The long non-coding RNA known as XIST regulates the process of Xchromosome inactivation in mammals. This is a key process in early embryogenesis that involves the silencing of one X chromosome in females and it is necessary for further development into viable offspring. The mechanism of regulation of this process is not entirely understood but is key to understanding development and fertility and broader evolutionary processes.
This project will address the functional molecular complexes a lncRNA forms in vivo using a number of omics technologies (RNA-Seq and Mass Spectrometry) in combination with reproductive and evolutionary biology approaches. There is the opportunity to take advantage of the University’s recent £16 million investment in the Astbury Biostructure Laboratory to assist this molecular characterization.
The questions this project will addresses are:
-What RNAs, DNAs and proteins does XIST interact with in vivo for silencing of the X chromosome?
-How do these interactions differ across embryos from different mammals?
-Do these interactions that we observe in XIST differ across these diverse placental and embryo types?

Background:
In eutherian mammals, X-chromosome inactivation (XCI) is required in females to ensure equal transcription levels of most X-linked genes for both males and females. In female (XX) preimplantation embryos, both X-chromosomes are transcriptionally active from embryonic genome activation until a long non-coding RNA (X-inactive specific transcript: XIST) mediates the inactivation of one. We know that species with different types of placental development have substantial diversity in the timing and regulation of XCI initiation but we do not know how this process works.

Objectives:
1-To determine the RNA, DNA and protein components that XIST interacts with in embryos from different placental phenotypes.
2-To integrate interaction data and extract the mechanism/s of function of XIST as it relates to placental evolution.
3-To identify evolutionary conserved and divergent molecular mechanisms in the XIST functional complex across different placental and embryo phenotypes.

Novelty:
This cutting edge project combines reproductive biology, RNA biology and computational evolutionary biology to address the fundamental questions of how the lncRNA XIST regulates XCI and the evolution of the mechanism across different placental types.

Timeliness:
This will be the first time the functional evolution of lncRNAs will be addressed in vivo. The in vivo pull-down methods are at the cutting edge of transcriptomic and proteomic technologies. Our recently founded LeedsOmics will provide the bioinformatics training required.

Experimental Approaches:
Embryos from mouse, bovine, sheep and pig (i.e. different placenta types) will be cultured with sex-sorted semen where possible. Lysates will be generated from the female embryos and then XIST RNA will be pulled-down with anti-sense biotinylated oligos (in vivo). The components of these XIST complexes will be identified by nano-LC MS/MS (proteins), RNA-seq (RNA) and ChIP-Seq (DNA). Resulting NGS data will be analysed computationally and will be compared to high quality mammal genomes to identify regions of conservation and variation.

Supervisors:
Dr Julie Aspden (http://aspdenlab.weebly.com/) (http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Aspden_J) [email protected]
Dr Niamh Forde (http://uafsupport.leeds.ac.uk/staff/naimh-forde/) [email protected]
Dr Mary O’Connell (http://mol-evol.org/mary-oconnell) (http://www.fbs.leeds.ac.uk/staff/profile.php?tag=OConnell_M) [email protected]

http://www.leedsomics.org/

Funding Notes

BBSRC White Rose Mechanistic Biology DTP 4 year studentship.
Studentships covers UK/EU fees and stipend (c.£14,296) for 4 years to start in Oct 2017. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.
Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.
There are 2 stages to the application process. Please see our website for more information: http://www.fbs.leeds.ac.uk/postgraduate/phdopportunities.php

References

Aspden, J. L., Eyre-Walker, Y. C., Philips, R., Amin, U., Mumtaz, A. S., Brocard, M., Couso, J. P. Extensive translation of small ORFs revealed by Poly-Ribo-Seq. eLife 10.7554/eLife.03528 (2014).

Rogulja-Ortmann, A., Picao-Osorio, J., Villava, C., Patraquim, P., Lafuente, E., Aspden, J., Thomsen, S., Technau, G.M. and Alonso, C.R. The RNA binding protein ELAV/Hu regulates Hox RNA processing, expression and function within the Drosophila nervous system. Development 141:2046-56 (2014).

Forde N*, Maillo V, Ó Gaora P, Simintiras CA, Sturmey RG, Ealy AD, Spencer
TE, Gutierrez-Adan A, Rizos D, Lonergan P. Sexually Dimorphic Gene Expression in Bovine Conceptuses at the Initiation of Implantation. Biol Reprod. 2016 Aug 3. pii: biolreprod.116.139857.

Tarver JE*, dos Reis M, Mirarab S, Moran RJ, Parker S, King BL, O’Connell MJ, Asher RJ, Warnow T, Peterson KJ, Donoghue PCJ and Pisani D* (2016). The Interrelationships of Placental Mammals and the Limits of Phylogenetic Inference. Genome Biology and Evolution. 2016 Jan 5;8(2):330-44. doi: 10.1093/gbe/evv261. (F1000 recommended)

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