Epigenetic drivers of Glial Toxicity in Progressive Multiple Sclerosis (P-MS)

Summary

Progressive MS is characterized by chronic neuroinflammation and progressive neurodegeneration driven by glial cell dysfunction, particularly within senescent Disease-Associated Radial Glia-like cells (DARGs).

This project will investigate the role of epigenetic mechanisms in driving DARG toxicity and neuroinflammation using patient-derived stem cell models. The student will develop advanced skills in multi-omics data analysis, bioinformatics, and 3D organoid culture. 

The research will leverage the established findings showing that P-MS iNSCs and fibroblasts exhibit distinct epigenetic profiles associated with senescence and inflammation.

Project aims

  1. Characterize epigenetic alterations in 2D and 3D P-MS models: Using genome-wide bisulfite sequencing (WGBS), ATAC-seq, and ChIP-seq to analyze DNA methylation, chromatin accessibility, and histone modifications in 2D iNSC cultures and 3D brain organoids. Focus on differentially methylated regions (DMRs) and differentially accessible regions (DARs) in genes relevant to inflammation and senescence. Compare findings with healthy controls.
  2. Identify key epigenetic regulators: Use bioinformatic analyses, including gene regulatory network (GRN) inference and pathway enrichment analysis, to pinpoint transcription factors and epigenetic modifiers contributing to the DARG phenotype. Investigate the interplay between epigenetic changes, gene expression, and cellular senescence/inflammation pathways.
  3. Investigate epigenetic instability: Assess the genomic integrity in P-MS models using whole-genome sequencing to identify mutations or genomic rearrangements potentially contributing to epigenetic instability. Explore the link between epigenetic instability, mitochondrial dysfunction (as described in related work), and disease progression.
  4. Validate findings in 3D organoids: Employ 3D brain organoids as a more physiologically relevant model to study cell-cell interactions and the spatial context of epigenetic changes. Correlate epigenetic profiles within the 3D organoids with functional changes in cell behaviour and inflammatory responses.

The project will ultimately contribute to a deeper understanding of the epigenetic mechanisms underlying glial cell toxicity in P-MS, offering opportunities for novel therapeutic interventions targeting epigenetic alterations to limit DARG formation and mitigate neuroinflammation.

References

  1. Ionescu RBN, A.M.; Reisz, J.A.; Williams, E.C.; Prasad, P.; Dzieciatkowska, M.;  Stephenson, D.; Suarez Cubero, M.; Pirvan, L.; Willis, C.M.; Peruzzotti-Jametti, L.;  Fossati, V.; Edenhofer,  F.; Leonardi, T.; Frezza, C.; Mohorianu, I. D’Alessandro, A.; Pluchino S. Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis. biorxv 2024. DOI: https://doi.org/10.1101/2024.01.16.575826.
  2. Park B. NAM, Tsitsipatis D., Pirvan L., Prasad P., Lopez De Novales M.L., Whitten J., Culig L., Llewellyn J., Ionescu R.B., Willis C.M., Krzak G., Fan J., De S., Suarez Cubero M., Spathopoulou A., Peruzzotti-Jametti L.,  Leonardi T., Edenhofer F.,  Gorospe M., Mohorianu I., Pluchino S., Beerman I. Integrative single-cell analysis of neural stem/progenitor cells reveals epigenetically dysregulated interferon response in progressive multiple sclerosis. bioRxiv 2024. DOI: https://doi.org/10.1101/2024.02.09.579648.
  3. Schirmer L, Schafer DP, Bartels T, et al. Diversity and Function of Glial Cell Types in Multiple Sclerosis. Trends Immunol 2021; 42: 228-247. 20210213. DOI: 10.1016/j.it.2021.01.005.
  4. Absinta M, Maric D, Gharagozloo M, et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature 2021; 597: 709-714. 20210908. DOI: 10.1038/s41586-021-03892-7.
  5. Schirmer L, Velmeshev D, Holmqvist S, et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 2019; 573: 75-82. 20190717. DOI: 10.1038/s41586-019-1404-z.

Contact details

Professor Stefano Pluchino - spp24@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

  • PhD