Fantastic proteins and where to find them: exploring the biology of histones outside the nucleus

Histone proteins package DNA within the confines of the nucleus in a macromolecular structure called chromatin. They additionally modulate the accessibility of DNA to gene and epigenetic regulators through the chemical modifications they carry (post-translational modifications, PTMs). Beyond their fundamental functions in genome packaging and regulation, histones have a life outside the nucleus: they are potent antimicrobial agents and the externalization of chromatin as an immune defense mechanism is a process that is as ancient and widespread across three of life as chromatin itself 1,2. We have discovered that histones are externalized in previously unappreciated contexts, beyond immune cells and immune defense. This discovery opens a new frontier in cell biology and the study of chromatin.

Our lab focusses on the study of histone citrullination3, the only known PTM specifically associated with histone externalization – indeed, extracellular histones are practically impossible to detect with confidence using current analytical methods, but citrullination can be used as a beacon that helps us locate this particular histone pool. Using tools and systems we have developed for the study of citrullination4-8, we are well placed to investigate the biology of extracellular histones in a variety of physiological or pathophysiological contexts.

This project will investigate the biology of histone externalization during tissue development, homeostasis and ageing. The work will be organized in three specific aims, which will address the following questions:

1) What is the mechanism of tissue externalization?

We will employ cell biological and biochemical analyses, coupled with powerful imaging technologies, to understand the pathways through which citrullination is activated and histones are externalized.

2) What are the consequences of extracellular histone sensing by neighbouring cells?

We will employ protein biochemistry and genome sequencing technologies to understand the signalling, transcriptomic and epigenetic changes undergone by cells that come in contact with extracellular histones. Our findings so far indicate that these cell responses differ drastically depending the age of the recipient cells, thus this aim will allow us to investigate how cell resilience is eroded during ageing.

3) Which molecular pathways mediate the responses to extracellular histone?

Using the readouts identified in Aim 2 and high-resolution proteomic analyses, we will aim to identify the molecules that mediate extracellular histone responses.

Through this research we will investigate a novel type of cell communication and its roles in mammalian development and ageing. The student who undertakes this work will obtain training in cell and developmental biology, protein biochemistry, genomics, proteomics, state-of-the-art imaging and bioinformatic analyses. Although we have a particular interest in developmental biology, tissue stem cells and ageing, the student joining our lab will have the opportunity to incorporate their own interests and inform the direction of their project.

Principal Supervisor

Dr Maria Christophorou

Email address: Maria.Christophorou@babraham.ac.uk

Competition funded studentship (unfunded) – You will need to apply for your own funding, possible sources of funding include the University of Cambridge-wide funding competitions, such as the Gates Cambridge Trust and Cambridge Trust (please visit the University of Cambridge Funding Search webpage). Please ensure you check the postgraduate funding competition box when applying.

URL link to personal profile page or website: Maria Christophorou | Babraham Institute

The applications deadline for all PhD studentships: 8th December 2027

Please note interviews will be held the week commencing 18th January 2027

Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University. Incomplete applications will not be considered.

Funding Notes

This studentship is a competition funded studentship (unfunded) and so you will need to apply for your own funding. Possible sources of funding include the University of Cambridge-wide funding competitions, such as the Gates Cambridge Trust and Cambridge Trust (please visit the University of Cambridge Funding Search webpage).

Please ensure you check the postgraduate funding competition box when applying.

References

References:
1. Sollberger G., Tilley D.O., Zychlinsky A. (2018). Neutrophil Extracellular Traps: The biology of chromatin externalization. Dev Cell 44(5):542-553. doi: 10.1016/j.devcel.2018.01.019. PMID: 29533770.
2. Grinat J., Shriever, N.P., Christophorou M.A. (2024). Fantastic proteins and where to find them – histones, in the nucleus and beyond. J Cell Sci, 137(24):jcs262071. doi: 10.1242/jcs.262071. PMID: 39704565.
3. Christophorou M.A. (2022). The virtues and vices of protein citrullination. R Soc Open Sci. 9(6):220125. doi: 10.1098/rsos.220125. PMID: 35706669.
4. Christophorou, M.A.*, Castelo-Branco, G.*, Halley-Stott, R., Slade Oliveira C., Loos R., Radzisheuskaya A., Mowen K., Bertone P., SIlva J.C.R., Zernicka-Goetz M., Nielsen M.L., Gurdon J.B., Kouzarides T. (2014). Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature 507:104–108. doi: 10.1038/nature12942. PMID: 24463520.
5. Cummings T.F.M., Gori K., Sanchez-Pulido L., Gavriilidis G., Moi D., Wilson A.R., Murchison E., Dessimoz C., Ponting C.P., Christophorou M.A. (2022). Citrullination Was Introduced into Animals by Horizontal Gene Transfer from Cyanobacteria. Mol Biol Evol. 39(2):msab317. doi: 10.1093/molbev/msab317. PMID: 34730808.
6. Singh A., Khan S., Moore D., Andrews S., Christophorou M.A. (2023). Transcriptomic analysis of PADI4 target genes during multi-lineage differentiation of embryonic stem cells. Philos Trans R Soc Lond B Biol Sci, 378(1890): 20220236. doi: 10.1098/rstb.2022.0236. PMID: 37778387.
7. Bertran M.T.*, Walmsley R.*, Cummings T., Aramburu I.V., Benton D.J., Mora Molina R., Assalaarachchi J., Chasampalioti M., Swanton T., Joshi D., Federico S., Okkenhaug H., Yu L., Oxley D., Walker S., Papayannopoulos V., Suga H., Christophorou M.A.**, Walport L.J.** (2024). A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation. Nat Commun. 15(1):9746. doi: 10.1038/s41467-024-53554-1. PMID: 39528459.
8. Rebak A.S., Hendriks I.A., Elsborg J.D., Buch-Larsen S.C., Nielsen C.H., Terslev L., Kirsch R., Damgaard D., Doncheva N.T., Lennartsson C., Rykær M., Jensen L.J., Christophorou M.A., Nielsen M.L. (2024). A quantitative and site-specific atlas of the citrullinome reveals widespread existence of citrullination and insights into PADI4 substrates. Nat Struct Mol Biol. 31(6):977-995. doi: 10.1038/s41594-024-01214-9. PMID: 38321148.