Lysine-specific demethylases as modulators of CNS glia cell function and neurodegeneration

Project Summary

Microglia are tissue macrophages of the central nervous system (CNS) and the epigenetic mechanisms that govern microglia function are poorly understood. Preliminary data reveal that both Kdm1a and Kdm4a are induced during CNS development and their inhibition strongly affects microglial cell function. We will therefore investigate the role of Kdm1a and Kdm4a by deletion in microglia during development and characterise the chromatin landscapes during neurodegeneration. Taken together, this project aims to identify epigenetic factors that affect the function of CNS cells in pathology.

Selected project-relevant publications

• Schwabenland M., Mossad O., Sievert A., Peres A.G., Ringel E., Baasch S., Kolter J., Cascone G., Dokalis N., Vlachos A., Ruzsics Z., Henneke P., Prinz M. and Blank T. (2023) Neonatal immune challenge poses a sex-specific risk for epigenetic microglial reprogramming and behavioral impairment. Nat Commun 14, 2721.
• Gulen M.F., Samson N., Keller A., Schwabenland M., Liu C., Glück S., Thacker V.V., Favre L., Mangeat B., Kroese L.J., Krimpenfort P., Prinz M. and Ablasser A. (2023) cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature 620, 374-380.
• Drougard A., Ma E.H., Wegert V., Sheldon R., Panzeri I., Vatsa N., Apostle S., Fagnocchi L., Schaf J., Gossens K., Völker J., Pang S., Bremser A., Dror E., Giacona F., Sagar, Henderson M.X., Prinz M., Jones R.G. and Pospisilik J.A. (2023) A rapid microglial metabolic response controls metabolism and improves memory. bioRxiv doi 10.1101/2023.04.03.535373.
• Masuda T., Amann L., Monaco G., Sankowski R., Staszewski O., Krueger M., Del Gaudio F., He L., Paterson N., Nent E., Fernández-Klett F., Yamasaki A., Frosch M., Fliegauf M., Bosch L.F.P., Ulupinar H., Hagemeyer N., Schreiner D., Dorrier C., Tsuda M., Grothe C., Joutel A., Daneman R., Betsholtz C., Lendahl U., Knobeloch K.P., Lämmermann T., Priller J., Kierdorf K. and Prinz M. (2022) Specification of CNS macrophage subsets occurs postnatally in defined niches. Nature 604, 740-748.
• Wieghofer P., Hagemeyer N., Sankowski R., Schlecht A., Staszewski O., Amann L., Gruber M., Koch J., Hausmann A., Zhang P., Boneva S., Masuda T., Hilgendorf I., Goldmann T., Böttcher C., Priller J., Rossi F.M., Lange C. and Prinz M. (2021) Mapping the origin and fate of myeloid cells in distinct compartments of the eye by single-cell profiling. EMBO J e105123.
• Koelsche C., … Staszewski O., Prinz M., …, Pfister S.M. and Von Deimling A. (2021) Sarcoma classification by DNA methylation profiling. Nat Commun 12, 498.
• Chhatbar C. and Prinz M. (2021) The roles of microglia in viral encephalitis: from sensome to therapeutic targeting. Cell Mol Immunol 18, 250-258.
• Sheikh B.N., Guhathakurta S., Tsang T.H., Schwabenland M., Renschler G., Herquel B., Bhardwaj V., Holz H., Stehle T., Bondareva O., Aizarani N., Mossad O., Kretz O., Reichardt W., Chatterjee A., Braun L.J., Thevenon J., Sartelet H., Blank T., Grün D., Von Elverfeldt D., Huber T.B., Vestweber D., Avilov S., Prinz M., Buescher J.M. and Akhtar A. (2020) Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature. Nat Cell Biol 22, 828-841.
• Geirsdottir L., David E., Keren-Shaul H., Weiner A., Bohlen S.C., Neuber J., Balic A., Giladi A., Sheban F., Dutertre C.A., Pfeifle C., Peri F., Raffo-Romero A., Vizioli J., Matiasek K., Scheiwe C., Meckel S., Mätz-Rensing K., Van Der Meer F., Thormodsson F.R., Stadelmann C., Zilkha N., Kimchi T., Ginhoux F., Ulitsky I., Erny D., Amit I. and Prinz M. (2020) Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program. Cell 181, 746.
• Erny D. and Prinz M. (2020) How microbiota shape microglial phenotypes and epigenetics. Glia 68, 1655-1672.
• Masuda T., Sankowski R., Staszewski O., Bottcher C., Amann L., Sagar, Scheiwe C., Nessler S., Kunz P., Van Loo G., Coenen V.A., Reinacher P.C., Michel A., Sure U., Gold R., Grun D., Priller J., Stadelmann C. and Prinz M. (2019) Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388-392.
• Jordao M.J.C., Sankowski R., Brendecke S.M., Sagar, Locatelli G., Tai Y.H., Tay T.L., Schramm E., Armbruster S., Hagemeyer N., Gross O., Mai D., Cicek O., Falk T., Kerschensteiner M., Grun D. and Prinz M. (2019) Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, doi: 10.1126/science.aat7554.
• Datta M., Staszewski O., Raschi E., Frosch M., Hagemeyer N., Tay T.L., Blank T., Kreutzfeldt M., Merkler D., Ziegler-Waldkirch S., Matthias P., Meyer-Luehmann M. and Prinz M. (2018) Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner. Immunity 48, 514-529.e516.
• Tay T.L., Mai D., Dautzenberg J., Fernandez-Klett F., Lin G., Sagar, Datta M., Drougard A., Stempfl T., Ardura-Fabregat A., Staszewski O., Margineanu A., Sporbert A., Steinmetz L.M., Pospisilik J.A., Jung S., Priller J., Grun D., Ronneberger O. and Prinz M. (2017) A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci 20, 793-803.
• Erny D. and Prinz M. (2017) Microbiology: Gut microbes augment neurodegeneration. Nature 544, 304-305.
• Biber K., Moller T., Boddeke E. and Prinz M. (2016) Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat Rev Drug Discov 15, 110-124.
• Goldmann T., Zeller N., Raasch J., Kierdorf K., Frenzel K., Ketscher L., Basters A., Staszewski O., Brendecke S.M., Spiess A., Tay T.L., Kreutz C., Timmer J., Mancini G.M., Blank T., Fritz G., Biber K., Lang R., Malo D., Merkler D., Heikenwalder M., Knobeloch K.P. and Prinz M. (2015) USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J 34, 1612-1629.
• Ginhoux F. and Prinz M. (2015) Origin of microglia: current concepts and past controversies. Cold Spring Harb Perspect Biol 7, a020537.
• Erny D., Hrabe De Angelis A.L., Jaitin D., Wieghofer P., Staszewski O., David E., Keren-Shaul H., Mahlakoiv T., Jakobshagen K., Buch T., Schwierzeck V., Utermohlen O., Chun E., Garrett W.S., Mccoy K.D., Diefenbach A., Staeheli P., Stecher B., Amit I. and Prinz M. (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18, 965-977.
• Staszewski O. and Prinz M. (2014) Glial epigenetics in neuroinflammation and neurodegeneration. Cell Tissue Res 356, 609-616.