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The role of RNA methylation in the development of the oocyte and preimplantation embryo.

PGR-P-186

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr John Huntriss and Professor Helen Picton
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Cardiovascular and Metabolic Medicine
<h2 class="heading hide-accessible">Summary</h2>

RNA methylation is a form of epitranscriptomic modification that modifies several RNA properties including stability, translation, splicing, transport and localization [1]. N6-methyladenosine (m6A) RNA methylation is the most prominent mark on messenger RNA (mRNA) and is known to regulate mRNA stability [2], making it a good candidate mark for the regulation of mRNA transcripts during the oocyte to embryo transition. A number of players in the m6A RNA methylation machinery have been identified. Thus, N6-methyladenosine (m6A) RNA methylation is mediated by the &amp;lsquo;writers&amp;rsquo; METTL3, METTL14, WTAP, which are RNA methyltransferases that methylate adenosine residues within RNA molecules to form m6A. Further, m6A is &amp;lsquo;erased&amp;rsquo; by RNA demethylases FTO and ALKBH5 and m6A marks are &amp;lsquo;read&amp;rsquo; by YTHDF1, YTHDF2 and YTHDF3. Collectively, these factors control gene expression by virtue of their involvement in m6A RNA methylation [3].

<h2 class="heading hide-accessible">Full description</h2>

<p>There is growing evidence of an essential role of RNA methylation in reproduction, during gametogenesis and early development. For example, mice deficient in the RNA demethylases ALKBH5 have increased m(6)A in their mRNA and consequently have impaired fertility and altered expression of transcripts regulating spermatogenesis [4]. Very recently, the RNA m6A reader YTHDF2 has been shown to be essential for oocyte competence and the post-transcriptional regulation of the oocyte transcriptome [5].</p> <p>This PhD studentship aims to establish the precise role(s) of at least one member of the RNA methylation machinery and will hence explore the role of epitranscriptomic processes in the regulation of mammalian oogenesis and embryogenesis. The bovine reproductive model will be used as a model for human reproduction. The favoured targets for knockdown are currently METTL14, WTAP, and YTHDF3. The functional impact of gene knock-down will be studied in the bovine oocyte and preimplantation embryo by knocking the gene(s) down in oocytes using DsiRNAs. Changes in the oocyte and embryonic transcriptome and, if possible, the m6A RNA methylome will be assessed to reveal gene pathways that are affected to hopefully give valuable insight into the role of RNA methylation in reproduction. Embryonic development after knockdown will be assessed using for example, time-lapse techniques and/or other established metrics of embryo development. The project will also map the expression patterns of m6A RNA methylation machinery gene transcripts and proteins in bovine tissues, ovarian follicles, oocytes and preimplantation embryos.</p> <p>The student will receive training in a range of cellular and molecular techniques that are applicable across many themes in biomedical research. These include molecular biology, including transcriptome analysis (for example: real time PCR, cDNA library generation from single oocytes/embryos and single cells, RNA sequencing). In addition the student will be trained in techniques in reproductive biology (for example: oocyte in vitro maturation (IVM), in vitro fertilization (IVF), preimplantation embryo culture and microinjection). In summary, these experiments will attempt to dissect the role of (m6A) RNA methylation machinery in mammalian oogenesis and preimplantation development.</p> <p><strong>References:</strong></p> <p>Liebers R, Rassoulzadegan M, Lyko F. Epigenetic regulation by heritable RNA. PLoS Genet. 2014 10(4):e1004296.</p> <p>N6-methyladenosine-dependent regulation of messenger RNA stability. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C. Nature. 2014 505(7481):117-20.</p> <p>Meyer KD, Jaffrey SR. The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol. 2014 15(5):313-26.</p> <p>Zheng G, Dahl JA, Niu Y, Fedorcsak P, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013 49(1):18-29.</p> <p>Ivanova I, Much C, Di Giacomo M, Azzi C. The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence. Mol Cell. 2017 67(6):1059-106.</p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete a<a href="https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form"> Faculty Application Form</a> and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If you have already applied for other projects using the Faculty Application Form this academic session you do not need to complete this form again. Instead you should email fmhgrad to inform us you would like to be considered for this project.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<h2 class="heading">Contact details</h2>

<p>For further information please contact the Graduate School Office<br /> e:<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>


<h3 class="heading heading--sm">Linked research areas</h3>