The interplay between lysine acetyltransferase MOF and ubiquitin ligase MSL2 in development and disease

Project Summary

The male specific lethal (MSL) complex is an evolutionarily conserved chromatin complex in flies and mammals. However, the role of the MSL2 protein in mammals remains unclear. In order to dissect MSL2 function, we plan to use female mouse embryonic stem cells and neural progenitor cells as an experimental model system. We aim to dissect the interplay of MOF and MSL2 in monoallelic versus biallelic gene expression to study dosage sensitivity of the targets in an allele specific manner. Taken together this proposal will provide novel insights into the allele-specific regulation by the mammalian MSL complex.

Selected project-relevant publications

• Tsang T.H., Wiese M., Helmstädter M., Stehle T., Seyfferth J., Shvedunova M., Holz H., Walz G. and Akhtar A. (2023) Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells. Sci Adv 9, eadh5598.
• Sun Y., Wiese M., Hmadi R., Karayol R., Seyfferth J., Martinez Greene J.A., Erdogdu N.U., Deboutte W., Arrigoni L., Holz H., Renschler G., Hirsch N., Foertsch A., Basilicata M.F., Stehle T., Shvedunova M., Bella C., Pessoa Rodrigues C., Schwalb B., Cramer P., Manke T. and Akhtar A. (2023) MSL2 ensures biallelic gene expression in mammals. Nature, doi 10.1038/s41586-023-06781-3.
• Iyer S.S., Sun Y., Seyfferth J., Manjunath V., Samata M., Alexiadis A., Kulkarni T., Gutierrez N., Georgiev P., Shvedunova M. and Akhtar A. (2023) The NSL complex is required for piRNA production from telomeric clusters. Life Sci Alliance 6, doi 10.26508/lsa.202302194.
• Guhathakurta S., Erdogdu N.U., Hoffmann J.J., Grzadzielewska I., Schendzielorz A., Seyfferth J., Mårtensson C.U., Corrado M., Karoutas A., Warscheid B., Pfanner N., Becker T. and Akhtar A. (2023) COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function. Nat Metab doi 10.1038/s42255-023-00904-w.
• Shvedunova M. and Akhtar A. (2022) Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol 23, 329-349
• Valsecchi C.I.K., Basilicata M.F., Georgiev P., Gaub A., Seyfferth J., Kulkarni T., Panhale A., Semplicio G., Manjunath V., Holz H., Dasmeh P. and Akhtar A. (2021) RNA nucleation by MSL2 induces selective X chromosome compartmentalization. Nature 589, 137-142.
• Pessoa Rodrigues C., Chatterjee A., Wiese M., Stehle T., Szymanski W., Shvedunova M. and Akhtar A. (2021) Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice. Nat Commun 12, 6212.
• Pessoa Rodrigues C. and Akhtar A. (2021) Differential H4K16ac levels ensure a balance between quiescence and activation in hematopoietic stem cells. Sci Adv 7, doi 10.1126/sciadv.abi5987.
• Karoutas A. and Akhtar A. (2021) Functional mechanisms and abnormalities of the nuclear lamina. Nat Cell Biol 23, 116-126.
• 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.
• Samata M., Alexiadis A., Richard G., Georgiev P., Nuebler J., Kulkarni T., Renschler G., Basilicata M.F., Zenk F.L., Shvedunova M., Semplicio G., Mirny L., Iovino N. and Akhtar A. (2020) Intergenerationally Maintained Histone H4 Lysine 16 Acetylation Is Instructive for Future Gene Activation. Cell doi 10.1016/j.cell.2020.05.026.
• Pessoa Rodrigues C., Herman J.S., Herquel B., Valsecchi C.I.K., Stehle T., Grün D. and Akhtar A. (2020) Temporal expression of MOF acetyltransferase primes transcription factor networks for erythroid fate. Sci Adv 6, eaaz4815.
• Lam K.C., Chung H.R., Semplicio G., Iyer S.S., Gaub A., Bhardwaj V., Holz H., Georgiev P. and Akhtar A. (2019) The NSL complex-mediated nucleosome landscape is required to maintain transcription fidelity and suppression of transcription noise. Genes Dev 33, 452-465.
• Karoutas A., Szymanski W., Rausch T., Guhathakurta S., Rog-Zielinska E.A., Peyronnet R., Seyfferth J., Chen H.R., De Leeuw R., Herquel B., Kimura H., Mittler G., Kohl P., Medalia O., Korbel J.O. and Akhtar A. (2019) The NSL complex maintains nuclear architecture stability via lamin A/C acetylation. Nat Cell Biol 21, 1248-1260.
• Valsecchi C.I.K., Basilicata M.F., Semplicio G., Georgiev P., Gutierrez N.M. and Akhtar A. (2018) Facultative dosage compensation of developmental genes on autosomes in Drosophila and mouse embryonic stem cells. Nat Commun 9, 3626.
• Basilicata M.F., Bruel A.L., Semplicio G., Valsecchi C.I.K., Aktas T., Duffourd Y., Rumpf T., Morton J., Bache I., Szymanski W.G., Gilissen C., Vanakker O., Ounap K., Mittler G., Van Der Burgt I., El Chehadeh S., Cho M.T., Pfundt R., Tan T.Y., Kirchhoff M., Menten B., Vergult S., Lindstrom K., Reis A., Johnson D.S., Fryer A., Mckay V., Fisher R.B., Thauvin-Robinet C., Francis D., Roscioli T., Pajusalu S., Radtke K., Ganesh J., Brunner H.G., Wilson M., Faivre L., Kalscheuer V.M., Thevenon J. and Akhtar A. (2018) De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nat Genet 50, 1442-1451.    
• Ilik I.A., Maticzka D., Georgiev P., Gutierrez N.M., Backofen R. and Akhtar A. (2017) A mutually exclusive stem-loop arrangement in roX2 RNA is essential for X-chromosome regulation in Drosophila. Genes Dev 31, 1973-1987.
• Aktas T., Avsar Ilik I., Maticzka D., Bhardwaj V., Pessoa Rodrigues C., Mittler G., Manke T., Backofen R. and Akhtar A. (2017) DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature 544, 115-119.
• Chatterjee A., Seyfferth J., Lucci J., Gilsbach R., Preissl S., Bottinger L., Martensson C.U., Panhale A., Stehle T., Kretz O., Sahyoun A.H., Avilov S., Eimer S., Hein L., Pfanner N., Becker T. and Akhtar A. (2016) MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria. Cell 167, 722-738.e723.
• Chlamydas S., Holz H., Samata M., Chelmicki T., Georgiev P., Pelechano V., Dundar F., Dasmeh P., Mittler G., Cadete F.T., Ramirez F., Conrad T., Wei W., Raja S., Manke T., Luscombe N.M., Steinmetz L.M. and Akhtar A. (2016) Functional interplay between MSL1 and CDK7 controls RNA polymerase II Ser5 phosphorylation. Nat Struct Mol Biol 23, 580-589.
• Ilik I.A., Quinn J.J., Georgiev P., Tavares-Cadete F., Maticzka D., Toscano S., Wan Y., Spitale R.C., Luscombe N., Backofen R., Chang H.Y. and Akhtar A. (2013) Tandem stem-loops in roX RNAs act together to mediate X chromosome dosage compensation in Drosophila. Mol Cell 51, 156-173.
• Conrad T., Cavalli F.M., Vaquerizas J.M., Luscombe N.M. and Akhtar A. (2012) Drosophila dosage compensation involves enhanced Pol II recruitment to male X-linked promoters. Science 337, 742-746.