Chromatin regulation of oncogenic transcription and replication stress: mechanism and functional implications in acute myeloid leukemia

Description

This project focuses on the molecular mechanisms promoting acute myeloid leukaemia (AML), a disease of great unmet need.

AML is an aggressive blood and bone marrow cancer characterized by abnormal proliferation and differentiation of myeloid cells. Despite extensive research, poor understanding of AML pathology has impeded the development of effective treatments, resulting in dismal survival rates.

AML is driven by dysregulated transcription and characterised by high levels of replication stress associated with replication defects and DNA damage. Dysregulated transcription is a major source of replication stress by interfering with the replication machinery. How conflicts between transcription and replication are resolved to enable AML growth is largely unknown.

We have demonstrated that the genome regulatory factor INO80 resolves transcription-replication conflicts to promote cancer cell proliferation (Prendergast et al., Nature Communications 2020). INO80 is overexpressed in AML, correlating with poor prognosis. Recent evidence indicates a critical role for INO80 in AML progression. Nevertheless, its mechanism remains unclear. This project will elucidate how INO80 promotes AML.

Experimental Approach

This is a cross-cutting collaboration between a Chromatin (Dr Papamichos-Chronakis), an AML Biology (Prof David MacEwan), and a Computational Biology (Dr Aditi Kanhere) team. The student will utilize lentiviral shRNA and CRISPR technologies to deplete INO80 and relevant factors in established AML cells lines and patient cells and employ a powerful combination of state-of-the-art and innovative genomics, transcriptomics and super-resolution microscopy technologies coupled with bioinformatics established in our teams.

Novelty and Impact

This project will reveal mechanisms of gene expression and maintenance of genome stability, providing a deeper understanding of AML pathogenesis. Dissecting pathways resolving transcription-replication conflicts forms a rational, innovative and promising approach for identifying targets for new therapeutic intervention.

Qualifications

The project is suited to a student with at least a good B.Sc. Upper Second in Biological or Life Sciences.

 

 

Applications will be reviewed from March 2024 until a suitable candidate is appointed.

Availability

Open to students worldwide

Funding information

Self-funded project

The project is open to both European/UK and International students. It is UNFUNDED and applicants are encouraged to contact the Principal Supervisor directly to discuss their application and the project.

Assistance will be given to those who are applying to international funding schemes.

The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of £5000 per year.

New self-funded applicants may be eligible for a tuition fees bursary.

Details of costs can be found on the University website:

https://www.liverpool.ac.uk/study/postgraduate-research/fees-and-funding/fees-and-costs/

Supervisors

References

  1. Prendergast L, McClurg UL, Hristova R, Berlinguer-Palmini R, Greener S, Veitch K, Hernandez I, Pasero P, Rico D, Higgins JMG, Gospodinov A, and Papamichos-Chronakis M. (2020). Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability. Nature Communications, 2020 Sep 10;11(1):4534. Selected as Editors Highlight. DOI: 10.1038/s41467-020-18306-x
  2. Luzzi S, Szachnowski U, Greener S, Schumacher K, Fulton S, Han KH, Darke J, Piccinno R, Lafon A, Pugh BF, Devys D, Tora L, Morillon A and Papamichos-Chronakis M (2021). Chromatin remodelling by INO80 at promoter proximal pause sites promotes premature termination of mRNA synthesis. bioRxiv https://doi.org/10.1101/2020.03.02.973685
  3. Lafon A*., Taranum S*., Pietrocola F., Dingli F., Damarys., Brahma S., Bartholomew B., and Papamichos-Chronakis M. (2015). INO80 Chromatin Remodeler Facilitates Release of RNA Polymerase II from Chromatin for Ubiquitin-Mediated Proteasomal Degradation. Molecular Cell, 60: 784–796. DOI: 10.1016/j.molcel.2015.10.028