Cross-talk between MECP2 post-translational modifications and MECP2 function upon glucocorticoid stress hormone stimulation
Final Report Abstract
MECP2 is the founding member of the methyl-CpG binding domain (MBD) protein family, specifically binds methylated CpGs via its MBD and is prominently localized in vivo at pericentric heterochromatin, highly enriched in heavily methylated major satellite DNA repeats. We have previously shown that MECP2 causes large-scale reorganization of heterochromatin by inducing its aggregation in a dose-dependent manner. We showed that mutations in the MECP2 gene, linked to the human neurological disorder Rett syndrome, affected its ability to bind and reorganized heterochromatin. Importantly, MECP2 was reported to be posttranslationally modified and was shown to undergo neuronal activity and stress-dependent phosphorylation. Current data provide support for MECP2 being one of the key mediators of stress-induced epigenetic changes affecting hippocampal function. However, very little is known about the fine tuning of this epigenetic reader in response to stress and how this translates into downstream cellular effects on chromatin structure and gene expression. In this project, we investigated MECP2 post-translational modifications that occur with and without stimulation with stress hormones and studied their role in regulating chromatin structure and gene activity. We focused on arginine methylation and phosphorylation, the latter as the best-studied MECP2 modification. We mapped these post-translational modifications in brain tissue and investigated their effect on MECP2: i) subcellular localization, ii) heterochromatin accumulation, iii) heterochromatin binding kinetics and, iv) heterochromatin organization.
Publications
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Zhang, P., Hastert, F. D., Ludwig, A. K., Breitwieser, K. Hofstaetter, M. and Cardoso, M. C.
(See online at https://doi.org/10.1093/biomethods/bpx010) - (2017). L1 retrotransposition is activated by Ten-eleventranslocation proteins and repressed by methyl-CpG binding domain proteins. Nucleus 8: 548-562
Zhang, P., Ludwig, A. K., Hastert, F. D., Rausch, C., Lehmkuhl, A., Hellmann, I., Smets, M., Leonhardt, H. and Cardoso, M. C.
(See online at https://doi.org/10.1080/19491034.2017.1330238) - (2017). Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain dependent manner. Nucleic Acids Res. 45: 7118-7136
Zhang, P., Rausch, C., Hastert, F. D., Boneva, B., Filatova, A., Patil, S. J., Nuber, U. A., Gao, Y, Zhao, X. and Cardoso, M. C.
(See online at https://doi.org/10.1093/nar/gkx281) - (2020). MeCP2 and chromatin compartmentalization. Cells 9:878
Schmidt, A., Zhang, H. and Cardoso, M.C.
(See online at https://doi.org/10.3390/cells9040878) - (2020). Validation strategies for antibodies targeting modified ribonucleotides. RNA 26: 1489-1506
Weichmann, F., Hett, R., Schepers, A., Ito-Kureha, T., Flatley, A., Slama, K., Hastert, F. D., Angstmann, N., Cardoso, M. C., König, J., Hüttelmaier, S., Dieterich, C., Canzar, S., Helm, M., Heissmeyer, V., Feederle, R. and Meister, G.
(See online at https://doi.org/10.1261/rna.076026.120) - (2022). MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid-liquid phase separation and restricted by DNA methylation. Nucleus
Zhang, H., Romero, H., Schmidt, A., Gagova, K., Qin, W., Bertulat, B., Lehmkuhl, A., Milden, M., Eck, M., Meckel, T., Leonhardt, H., Cardoso, M. C.
(See online at https://doi.org/10.1080/19491034.2021.2024691)
