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PhD Studentship: Memories from a Different Past: Role of Epigenetics in the Cell Biology of Sclerostin Deficiency

London Interdisciplinary Biosciences Consortium - Comparative Biomedical Sciences, Royal Veterinary College

Qualification Type: PhD
Location: London
Funding for: UK Students, EU Students, International Students
Funding amount: £20,622 per annum
Hours: Full Time
Placed On: 20th October 2023
Closes: 10th January 2024

Epigenetic changes are heritable modifications in gene expression without alterations in DNA sequences. It is well established that epigenetic remodelling is associated with disease and aging, but it is now emerging that epigenetics may also mediate memory of tissue-forming responses. Indeed, it has recently been shown that modification of DNA methylation following a single anabolic stimulus is responsible for muscle hypertrophy (growth) and that a ‘memory’ of this event is maintained for a long period (over 5 months; 1). We have discovered that skeletal cells display memory when extracted from a skeleton functioning under constant anabolic signalling (sclerostin deficiency), and speculate that this too is governed epigenetically. Sclerostin, encoded by SOST, is secreted by osteocytes and binds to LRP4/5/6 receptors on osteoblasts to inhibit Wnt/β-catenin signalling and bone formation. Mutations in SOST, or in regulatory elements, cause an increase in osteoblast-mediated bone formation and result in higher bone mass, as seen in conditions such as Sclerosteosis(2).

This studentship will define the role of epigenetics in memory imprinting of cells responsible for skeletal remodelling. Evidence that this memory arises epigenetically comes from our finding that expression of specific epigenetic enzymes is positively correlated with cell function. Manipulation of such epigenetic modulators may improve bone regeneration, which will have applications in age-related bone loss. This project will expose the successful candidate to a range of experimental techniques including cell biology, in vitro compound (pharmacodynamic) analysis, sequencing, bioinformatics/machine learning and drug development.

The successful applicant will be a member of the research group led by Dr Scott Roberts, which contains researchers aiming to understand mechanisms of skeletal dysfunction. They will also be part of the larger RVC Skeletal Biology Group, which consists of several inter-related research teams united by a common objective, to understand skeletal biology in health and disease. This studentship will be based at the RVC’s Camden campus in new purpose-built research laboratories.

This interdisciplinary collaborative project is partnered with Relation Therapeutics, a leader in the use of high-resolution biology, machine learning (ML) and clinical insights to discover life-changing medicines. The successful candidate will spend a 3-month placement at Relation Therapeutics flagship integrated wet–dry laboratory in London. The placement will expose the student to sophisticated functional genomic techniques with extraordinary computational power and ML.

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