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Regulatory genomics of multicellular processes


   MRC London Institute of Medical Sciences (LMS)

   Tuesday, December 14, 2021  Funded PhD Project (Students Worldwide)

About the Project

Regulation of gene expression is central to every aspect of biology - from the subcellular level, via the regulation of cell cycle, to the development of body plans and organ systems in multicellular organisms. Our group uses methods of computational and experimental biology to study gene regulation at the level of whole genomes, including the structure and function of gene promoters, proximal and distal regulatory elements, and the communication between them. In recent years, the approaches we developed have shed light on the role of large genomic regions showing aberrantly high levels of evolutionary conservation, genome wide promoter switching between somatic and germline cells, and  general grammar of DNA sequences of promoters that distinguishes promoters regulated at the level of individual cells from those regulated at the level of multicellular processes involving coordination across many cells.

In this project the student will address some of the key unanswered questions of gene regulation in multicellular animals: What makes some gene promoters respond to enhancers a megabase away from them, while other promoters ignore them? What makes a promoter more active in early vs. late stages of the cell cycle? How are typical “insulator” proteins repurposed to serve as integral part of promoter and enhancer architectures? All these questions are central to understanding the special features of regulation of multicellular processes underlying development, differentiation and cancer.

The student will receive training in both experimental methods of regulatory genomics (Cap analysis Gene Expression (CAGE), ATAC-seq, NET-seq and others) and computational methods to process and analyse this and publicly available experimental data, including applied statistics and machine learning. Biology and biomedicine have become quantitative, data-intensive sciences, and the ability to do both experimental and computational methods is central to successful future career. The ratio of experimental and computational work on the project is flexible and could be to an extent adopted to student’s background and interests.


Funding Notes

This funding covers tuition fees and also a stipend amounting to £21,000pa paid directly to the student, for 3.5 years in total.
Whilst there are no residency restriction for these studentships, there is more funding available for Home Fee students (including UK nationals and those with settled and pre-settled status until at least April 2026), which make the international studentships highly competitive

References

Cvetesic N, Borkowska M, Hatanaka Y, Leitch HG, Müller F, Yu C, Vincent SD, Tora L, Hajkova P, Lenhard B. 2020. Global regulatory transitions at core promoters demarcate the mammalian germline cycle. bioRxiv 11: 2020.10.30.361865. https://www.biorxiv.org/content/10.1101/2020.10.30.361865v1.
Cvetesic N, Leitch HG, Borkowska M, Müller F, Carninci P, Hajkova P, Lenhard B. 2018. SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA. Genome research 28: 1943–1956.
Haberle V, Li N, Hadzhiev Y, Plessy C, Previti C, Nepal C, Gehrig J, Dong X, Akalin A, Suzuki AM, et al. 2014. Two independent transcription initiation codes overlap on vertebrate core promoters. Nature 507: 381–385.
Harmston N, Ing-Simmons E, Tan G, Perry M, Merkenschlager M, Lenhard B. 2017. Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation. Nature communications 8: 441.
Polychronopoulos D, King JWD, Nash AJ, Tan G, Lenhard B. 2017. Conserved non-coding elements: developmental gene regulation meets genome organization. Nucleic acids research 45: 12611–12624.

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