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Robustness of the molecular programme that drives cellular differentiation during embryonic blood cell development


School of Life Sciences

About the Project

Our body consists of numerous cell types that all fulfil very specific functions. Cellular differentiation is the process by which these cells arise from immature precursor cells during embryogenesis. While all precursor cells carry the same genetic information, each of them makes differential use of this information as it gives rise to a mature cell. Gene regulators that control the expression of genes act in a large gene regulatory network. The connections in this network are hard-wired in our genome. During the differentiation of a cell into a specific cell type, only one part of gene regulatory network is activated. Which part this is depends on prior gene expression (intrinsic factors) and on influences from outside the cells (extrinsic factors). As a cell differentiates, it moves from one regulatory state to another. Each of them is defined by a set of gene regulators. As the cell enters a new state, it not only activates a new set of genes, it also extinguishes the previous state and suppresses alternative options. Gene activators push the cellular differentiation forward while gene repressors prevent cells from slipping back or taking alternative molecular trajectories. Together, they confer robustness to cellular differentiation and determine the pace of the process. Failure to establish or maintain robustness can lead to cellular deficiencies and cancer. Therefore, understanding how robustness is established and maintained is vitally important.

If you decide to join us on this project, you will study blood cell development during zebrafish embryogenesis. Zebrafish is a great in vivo vertebrate model that allows you to study the molecular processes that govern the formation of the embryo and the generation and maintenance of the adult organism. Using mutant fish lines, you will examine your favourite blood cell type in the presence or absence of your gene of interest. Transgenic reporter genes that encode fluorescent proteins will light up your favourite blood cells and allow you to trace their formation and behaviour in transparent zebrafish embryos. Following cellular dissociation, the fluorescent protein also allows you to isolate your cell type for in vitro studies. In these studies, you may interrogate the structure of your cells under the electron microscope or investigate the cells’ gene expression profile in RNA-sequencing experiments.

You can expect a large zebrafish aquarium to hold your mutant and transgenic zebrafish, a set of light, fluorescent and confocal microscopes to help you study your embryos, flow cytometric sorters that allow you to sort your cells, and numerous facilities that help you to perform the in vitro studies that you want to do. Among the latter, I would like to highlight the electron microscopy suit and the deep sequencing unit with its experts in bioinformatics.

References

Jessop, P. and Gering, M. (2021). Immunohistochemical detection of 5-Hydroxymethylcytosine and 5-carboxymethylcytosine in sections of zebrafish embryos. Methods Mol Biol. 2198, 193-208.

Moore, C., Richens, J.L., Hough, Y., Ucanok, D., Malla, S., Sang, F., Chen, Y., Elworthy, S., Wilkinson, R.N., and Gering, M. (2018). Gfi1aa and Gfi1b set the pace for primitive erythroblast differentiation from hemangioblasts in the zebrafish embryo. Blood Adv. 2, 2589–2606.

Jessop, P., Ruzov, A., and Gering, M. (2018). Developmental Functions of the Dynamic DNA Methylome and Hydroxymethylome in the Mouse and Zebrafish: Similarities and Differences. Front. Cell Dev. Biol. 6, 27, 1–15.

Thambyrajah, R., Ucanok, D., Jalali, M., Hough, Y., Wilkinson, R.N., McMahon, K., Moore, C., and Gering, M. (2016). A gene trap transposon eliminates haematopoietic expression of zebrafish Gfi1aa, but does not interfere with haematopoiesis. Dev. Biol. 417, 25–39.

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