Better (methy)late than never: Deciphering the role of DNA methylation in blood cell development

MOK_U23DTP1

Hematopoiesis is a dynamic process by which all blood cells are generated during the lifetime of an organism.

Blood cells are closely regulated by epigenetic changes through DNA methylation which governs gene expression and cellular fate and function.

Understanding how blood cells form is of fundamental importance and clinically relevant for the progress of cell replacement therapies and transplantation protocols in blood and vascular geneticand age-related diseases.

The earliest hematopoietic stem and progenitor cells (HSPCs) are generated from the ventral wall of the dorsal aorta through endothelial-to-hematopoietic transition during vertebrate embryogenesis. The precise control of DNA methylation during this process remains unclear.

In this project we will use in vivo assays (using the avian embryo as our model organism) to understand the roles of DNA methyltransferases (DNMTs) in early hematopoiesis – with genome editing tools – and utilise advanced sequencing technologies with colleagues at UEA and the Earlham Institute to map the global methylome dynamics during this process.

Many of the molecular processes involved in cellular reprogramming are conserved during evolution and is likely that at least some of the discoveries made in the avian model will have direct relevance to humans.

We are looking for an enthusiastic, creative and ambitious student to generate and analyse DNA methylation datasets and validate findings for in vivo functional analysis to better understand embryonic blood development.

The project is joint between groups of Gi Fay Mok and David Monk at the BioMedical Research Centre (UEA), Iain Macaulay and Wilfried Haerty (both at EI).

In addition to bench and bioinformatic training provided through this unique collaborative project, the student will acquire excellent personal and professional development training offered by UEA, EI and the NRPDTP.

Contact Dr Gi Fay Mok (g.mok@uea.ac.uk) for more information and discussions about the project.

References

Louise Smith, E., Mok, G. F., & Münsterberg, A. (2022). Investigating chromatin accessibility during development and differentiation by ATAC-sequencing to guide the identification of cis-regulatory elements. Biochemical Society transactions, 50(3), 1167–1177. https://doi.org/10.1042/BST20210834.

Mok, G. F., Folkes, L., Weldon, S. A., Maniou, E., Martinez-Heredia, V., Godden, A. M., Williams, R. M., SaukaSpengler, T., Wheeler, G. N., Moxon, S., &
Münsterberg, A. E. (2021). Characterising open chromatin in chick embryos identifies cis-regulatory elements important for paraxial mesoderm formation and axis extension. Nature communications, 12(1), 1157. https://doi.org/10.1038/s41467-021-21426-7.

Mok, G. F., McColl, J., & Münsterberg, A. (2021). 4D Live Imaging and Analysis of Chick Embryo Somites. Methods in molecular biology (Clifton, N.J.), 2179, 173–181. https://doi.org/10.1007/978-1-0716-0779-4_15.

Mok, G. F., Lozano-Velasco, E., Maniou, E., Viaut, C., Moxon, S., Wheeler, G., & Münsterberg, A. (2018). miR-133- mediated regulation of the Hedgehog pathway orchestrates embryo myogenesis. Development (Cambridge, England), 145(12), dev159657. https://doi.org/10.1242/dev.159657.

Goljanek-Whysall, K., Mok, G. F., Fahad Alrefaei, A., Kennerley, N., Wheeler, G. N., & Münsterberg, A. (2014). myomiR-dependent switching of BAF60 variant incorporation into Brg1 chromatin remodeling complexes during embryo myogenesis. Development (Cambridge, England), 141(17), 3378–3387. https://doi.org/10.1242/dev.108787.