Towards understanding the mechanisms linking preterm birth and neurodevelopmental disorders

Medical Research Scotland
PhD Studentship Award

This project is one of 15 four-year PhD Studentships funded by Medical Research Scotland (http://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and Company. The Studentships will provide the first-class academic and commercial training needed to equip the successful candidate for a science career in an increasingly competitive market.

"Understanding epigenetic mechanisms linking preterm birth and neurodevelopmental disorders" to be delivered by the University of Edinburgh and Aquila Biomedical Ltd (http://www.aquila-bm.com) [Company supervisor: Ms Clare Doris].

Preterm birth (PTB) affects ~11% of newborns and is associated with cerebral palsy, cognitive impairment, autism spectrum disorder and psychiatric disease. Although the underlying mechanisms are unclear, the effects of the environment on neurogenesis could be mediated through epigenetic alterations, including altered DNA methylation (5-methylcytosine: 5mC), which regulates gene expression and determines neural cell fate. Epigenetic dysregulation occurs in brains in animal models and humans after early-life adversity and may mediate gene-environment interactions between early-life stress and neuropsychiatric outcome. We have found altered 5mC at key neurodevelopmental genes in buccal cells after PTB (Sparrow S, in press).

Although there are concerns about the deleterious effects of early glucocorticoid exposure, glucocorticoids are used in threatened PTB because they reduce morbidity and mortality. However, follow-up studies suggest increased behavioural problems in childhood following repeated prenatal exposure and postnatal glucocorticoids are associated with an increased risk of cerebral palsy. Importantly, animal studies show that early glucocorticoid overexposure can alter DNA methylation.

Dynamic changes in the brain methylome occur throughout fetal life: DNA methyltransferases (Dnmts) lead to the production of 5mC, whilst Ten-eleven-translocase (Tet) enzymes catalyse demethylation, beginning with the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). 5hmC is most abundant in cerebellar Purkinje neurones where it facilitates demethylation during fetal development, however recent data shows that 5hmC is also a stable, functional modification which associates with transcriptional activation and can be used as an indicator of cell state during maturation. Studies showing Tet1 knockout mice exhibit abnormal behaviour, neurogenesis and increased neuronal sensitivity to oxidative stress demonstrate the importance of Tet1 in brain.

In mice, brain development at birth resembles a 24-week gestation fetus and matures to the equivalent of term babies by ~postnatal day (P)13, providing a window in which to study factors influencing brain development. We will focus on the effects of glucocorticoid exposure on the transcriptome and epigenome (5hmC) in the developing brain. The results will be relevant to our understanding of brain development in preterm infants (most are exposed to antenatal glucocorticoids) and also to term babies exposed to glucocorticoids prenatally because of a) threatened preterm labour or b) the therapeutic use of glucocorticoids for the management of congenital adrenal hyperplasia.

We will use a cerebellar slice model which maintains 3D cerebellar architecture and the cellular environment. The model is relevant, since the cerebellum is at particular risk of damage in PTB and cerebellar injury may contribute to the high rates of cognitive, behavioural, and motor deficits.

In this project the student will seek to address the hypotheses that pre- and postnatal glucocorticoids affect the transcriptome and epigenome of the developing brain and that these effects will be more substantial in Tet1 knockout mice.

ENQUIRIES:

Enquiries should be sent by email to Dr Mandy Drake:
[Email Address Removed]

APPLICATIONS:

Candidates must have obtained, or expect to obtain, a first or 2.1 UK BSc Honours degree, or equivalent for degrees obtained outside the UK, or a Masters qualification (merit or distinction) in an appropriate discipline.

Applicants should send a CV, the contact details of 2 references (including email addresses) and a covering letter, explaining why the applicant wishes to carry out this project, by email to:
Mrs Lynn Meikle
[Email Address Removed]

Interviews are expected to take place 3-4 weeks after the closing date for applications.

It is anticipated that the PhD Studentship will start in September 2016.