The epigenetics of degenerative rare diseases

58 million people worldwide are diagnosed with a rare developmental disorder (DD). While the diagnostic path is massively improving, the development of therapies and the understanding of the molecular mechanisms leading to a certain disease state are often still a long way off. The most enriched class of mutations in DD are chromatin machinery genes, as for the Basilicata-Akhtar syndrome. DNA and its accessory factors make up chromatin, which helps to pack the genome while also being subjected to a plethora of regulatory mechanisms that ultimately affect gene expression. Chromatin is largely studied in the context of processes occurring in the cell nucleus. However, it can also reflect on organelle communication (e.g. plasma membrane, mitochondria, ER, lysosomes), metabolism and finally on cellular interactions with the neighboring environment, aside from the direct modulation of gene expression. As part of the High Potential Grant, I will look at how mutations in chromatin-modifying complexes lead to common "rewiring" of organelles, which ultimately could explain the higher susceptibility to cardiometabolic and neurodegenerative comorbidities observed in DD patients.  I will employ a multidisciplinary approach looking at underlying molecular and cellular mechanisms, through the combination of embryonic stem cell culture, patterned organoids and in vivo models. The methods include CRISPR engineering, state-of-the-art multiomics, high-resolution microscopy and functional assays.

Mentor: Univ.-Prof. Dr. med. Susann Schweiger, Institute for Human Genetics

Publications:

1. Basilicata MF, Bruel A-L, Semplicio G, Valsecchi CIK, Aktaş T, Duffourd Y, Rumpf T, Morton J, Bache I, Szymanski WG, Gilissen C, Vanakker O, Õunap K, Mittler G, van der Burgt I, El Chehadeh S, Cho MT, Pfundt R, Tan TY, Kirchhoff M, Menten B, Vergult S, Lindstrom K, Reis A, Johnson DS, Fryer A, McKay V, DDD Study, Fisher RB, Thauvin-Robinet C, Francis D, Roscioli T, Pajusalu S, Radtke K, Ganesh J, Brunner HG, Wilson M, Faivre L, Kalscheuer VM, Thevenon J, 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. doi: 10.1038/s41588-018-0220-y

2. Valsecchi CIK*, Basilicata MF*, Georgiev P, Gaub A, Seyfferth J, Kulkarni T, Panhale A, Semplicio G, Manjunath V, Holz H, Dasmeh P, Akhtar A. 2021. RNA nucleation by MSL2 induces selective X chromosome compartmentalization. Nature. 589:137–142. doi: 10.1038/s41586-020-2935-z

3. Basilicata MF, Frank M, Solter D, Brabletz T, Stemmler MP. 2016. Inappropriate cadherin switching in the mouse epiblast compromises proper signaling between the epiblast and the extraembryonic ectoderm during gastrulation. Sci. Rep. 6:26562. doi: 10.1038/srep26562

4. Basilicata MF^#, Keller Valsecchi CI^#. 2021. The good, the bad, and the ugly: Evolutionary and pathological aspects of gene dosage alterations. PLoS Genet. 17(12):e1009906. doi: 10.1371/journal.pgen.1009906.

5. Samata M, Alexiadis A, Richard G, Georgiev P, Nuebler J, Kulkarni T, Renschler G, Basilicata MF, Zenk FL, Shvedunova M, Semplicio G, Mirny L, Iovino N, Akhtar A. 2020. Intergenerationally Maintained Histone H4 Lysine 16 Acetylation Is Instructive for Future Gene Activation. Cell. 182: 127-144.e23. doi: 10.1016/j.cell.2020.05.026

* Shared first authorship; ^# Co-corresponding authorship

Further information: will follow soon