In this episode of the Epigenetics Podcast, we caught up with Nada Jabado from McGill University to talk about her work on oncohistones as drivers of Pediatric Brain Tumors.

Nada Jabado and her team were amongst the first to identify mutations in Histone 3.3 Tails which lead to differentially remodeled chromatin in pediatric glioblastoma. Mutations that occur include the Lysine at position 27 and the Glycine at position 34. If those residues are mutated it will influence the equilibrium of chromatin associated proteins like the Polycomb Repressive Complex (PRC) and hence domains of heterochromatin will be shifted. This, in turn, will lead to differential gene expression and development of developmental disorders or cancer.

References

Schwartzentruber, J., Korshunov, A., Liu, X. Y., Jones, D. T., Pfaff, E., Jacob, K., Sturm, D., Fontebasso, A. M., Quang, D. A., Tönjes, M., Hovestadt, V., Albrecht, S., Kool, M., Nantel, A., Konermann, C., Lindroth, A., Jäger, N., Rausch, T., Ryzhova, M., Korbel, J. O., … Jabado, N. (2012). Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 482(7384), 226–231. https://doi.org/10.1038/nature10833

Kleinman, C. L., Gerges, N., Papillon-Cavanagh, S., Sin-Chan, P., Pramatarova, A., Quang, D. A., Adoue, V., Busche, S., Caron, M., Djambazian, H., Bemmo, A., Fontebasso, A. M., Spence, T., Schwartzentruber, J., Albrecht, S., Hauser, P., Garami, M., Klekner, A., Bognar, L., Montes, J. L., … Jabado, N. (2014). Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nature genetics, 46(1), 39–44. https://doi.org/10.1038/ng.2849

Papillon-Cavanagh, S., Lu, C., Gayden, T., Mikael, L. G., Bechet, D., Karamboulas, C., Ailles, L., Karamchandani, J., Marchione, D. M., Garcia, B. A., Weinreb, I., Goldstein, D., Lewis, P. W., Dancu, O. M., Dhaliwal, S., Stecho, W., Howlett, C. J., Mymryk, J. S., Barrett, J. W., Nichols, A. C., … Jabado, N. (2017). Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nature genetics, 49(2), 180–185. https://doi.org/10.1038/ng.3757

Chen, C., Deshmukh, S., Jessa, S., Hadjadj, D., Lisi, V., Andrade, A. F., Faury, D., Jawhar, W., Dali, R., Suzuki, H., Pathania, M., A, D., Dubois, F., Woodward, E., Hébert, S., Coutelier, M., Karamchandani, J., Albrecht, S., Brandner, S., De Jay, N., … Jabado, N. (2020). Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis. Cell, 183(6), 1617–1633.e22. https://doi.org/10.1016/j.cell.2020.11.012

Chaouch, A., Berlandi, J., Chen, C., Frey, F., Badini, S., Harutyunyan, A. S., Chen, X., Krug, B., Hébert, S., Jeibmann, A., Lu, C., Kleinman, C. L., Hasselblatt, M., Lasko, P., Shirinian, M., & Jabado, N. (2021). Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks. Molecular cell, 81(23), 4876–4890.e7. https://doi.org/10.1016/j.molcel.2021.10.008

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