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Lineage-specific factors that bookmark the genome to maintain epigenetic inheritance through mitosis

  • Full or part time
    Prof A Fisher
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

We are interested in how cells divide to generate daughters that share the same lineage and developmental state as their parent. While a lot is known about gene expression, chromatin state and transcription factors in cells during interphase, when chromosomes are extensively de-condensed, we know relatively little about these features in mitosis, when newly-replicated chromosomes de-condense, become spatially organised and then separate.

This project will examine the chromatin and transcription factor binding features of mitotic chromosomes that collectively ensure that epigenetic information is correctly passed on to daughter cells (1). We will examine mitotic chromsomes isolated from a range of different cell types; stem cells, committed progenitors and differentiated cells. We will take advantage of our recent discovery that Ikaros, a DNA binding factor critical for blood cell development (2), remains bound to native chromosomes through mitosis (Djeghloul et al., unpublished). We will use a range of bespoke genetic and epigenetic tools, advanced flow cytometry, microscopy, proteomics and miniaturised ‘cut and run’ approaches to examine how and where Ikaros bookmarks the mitotic genome. We will examine whether Ikaros remains bound to a subset of the genes that it regulates during interphase (3), as well as to heterochromatin domains surrounding centromeres (4). If so, we will ask what happens to cellular identity when Ikaros binding is impaired during mitosis.

These studies will investigate whether mitotic bookmarking by Ikaros and other critical transcriptional regulators, requires specific features of chromatin (such as methylated histone H3K9, H3K27 or DNA methylation) or whether this depends soley on the accessibility of sequence-specific DNA motifs on mitotic chromosomes.
This project will tackle a fundamental question in cell biology; epigenetic inheritance. The prevalence of Ikaros mutations in human leukaemias (5) however, suggests that discoveries made in these studies will have implications for predicting and tackling human haematopoietic diseases.

To Apply: Please visit our website (https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/) to download an application form.

Funding Notes

This project is one of multiple available projects potentially funded by the MRC. If successful the studentship would cover all tuition fee payments and includes a tax-free stipend amounting to £21,000pa (paid in monthly installments directly to the student) for 3.5 years.

Whilst this funding is available to students worldwide, due to the higher tuition fee rate of overseas students competition is higher and so only exceptional OS applicants will be considered.

References

Systematic identification of factors bound to isolated metaphase ESC chromosomes reveals a role for chromatin repressors in compaction
1. Dounia Djeghloul, AnneCéline Kohler, Bhavik Patel, Holger Kramer, Nicolas Veland, ChadWhilding, Andrew Dimond, James Elliott, Amelie Feytout, Tanmay A.M. Bharat, Abul K. Tarafder, Jan Löwe, BeeL.Ng, Ya Guo, Karen Brown, Jacky Guy, Matthias Merkenschlager, Amanda G. Fisher bioRxiv 750067; doi: https://doi.org/10.1101/750067

2. The Ikaros family in lymphocyte development. Heizmann B, Kastner P, Chan S. Curr Opin Immunol. 2018 Apr;51:14-23

3. Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation.
Ferreirós-Vidal I, Carroll T, Taylor B, Terry A, Liang Z, Bruno L, Dharmalingam G, Khadayate S, Cobb BS, Smale ST, Spivakov M, Srivastava P, Petretto E, Fisher AG, Merkenschlager M. Blood. 2013 Mar 7;121(10):1769-82

4. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin.
Brown KE, Guest SS, Smale ST, Hahm K, Merkenschlager M, Fisher AG.
Cell. 1997 Dec 12;91(6):845-54

5. Ikaros and leukaemia.
Olsson L, Johansson B. Br J Haematol. 2015 May;169(4):479-91.

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