Die High Potentials Grant Fellows der Universitätsmedizin Mainz werden für einen Zeitraum von 3 (medical scientists, PhD) bzw. 4 Jahren (clinician scientists, MD) mit einem Gesamtbudget von 300.000 € gefördert.
Im Folgenden stellen wir Ihnen die bisherigen Fellows und ihre Projekte in Kurzprofilen vor.
Falls Sie Interesse daran haben, selbst eine/n Kandiat_in zu nominieren oder sich nominieren zu lassen, finden Sie auf dieser Seite alle Informationen bezüglich Nominierungskriterien, Verfahren und einzureichender Unterlagen.
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
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
Cohesin deficiency and myeloid expansion: from mechanisms of action to novel therapeutic routes
Almost 50% of all acute myeloid leukemias (AML) in elderly patients occur secondary to age-related pre-leukemic conditions known as myelodysplastic syndromes (MDS). The evolution from MDS to AML ultimately leads to a dismal prognosis. Recent evidence has shown that cohesin member mutations predispose towards premature hematopoietic aging, MDS and leukemic progression. Cohesin is an epigenetic complex that controls the interaction between promoters and enhancers and, therefore, supervises transcription.
We and others have shown that cohesin actively maintains gene regulatory homeostasis, with deficiency of cohesin subunits preferentially impairing inducible gene expression, such as the terminal erythroid differentiation, lymphoid maturation or interferon response. Conversely, our newer data show that cohesin is dispensable for the myeloid commitment. Moreover, cohesin-deficient myeloid progenitors surprisingly express abundant H3K27ac (an activation histone mark) at myeloid development genes, where they redistribute the remaining cohesin. These events phenotypically lead to myeloid expansion. We note a similar pattern in a murine Flt3-ITD/Npm1c AML model. Here, cohesin perturbation upregulates a transcriptional program of immune checkpoints and leukemic stem cell (LSC) markers and causes an increase of >100x the number of LSCs.
With this project, I propose that a comprehensive evaluation of causes and paths of cohesin deficiency-associated myeloid proliferation, both in normal hematopoiesis and in models of MDS and AML, will identify opportunities of prevention of AML progression. Based on this hypothesis, I aim to discover the mechanisms that dictate the myeloid expansion in cohesin deficient hematopoiesis and establish therapeutic strategies to either prevent disease progression or to specifically target cohesin-mutated myeloid neoplasia.
Mentor: Univ.-Prof. Dr. med. Matthias Theobald, III. Medical Department (Hematology, Oncology, Pneumonology)
1. Sasca D, Yun H, Giotopoulos G, Szybinski J, Evan T, Wilson NK, Gerstung M, Gallipoli P, Green AR, Hills R, Russell N, Osborne CS, Papaemmanuil E, Göttgens B, Campbell P, Huntly BJP. Cohesin-dependent regulation of gene expression during differentiation is lost in Cohesin-mutated myeloid malignancies. Blood. 134 (24), 2195-2208 2019 Dec 12.
2. Sasca D, Szybinski J, Schüler A, Shah V, Heidelberger J, Haehnel PS, Dolnik A, Kriege O, Fehr EM, Gebhardt WH, Reid G, Scholl C, Theobald M, Bullinger L, Beli P, Kindler T. NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML. Blood. 2019 May 23;133(21):2305-2319.
3. Sasca D, Hähnel PS, Szybinski J, Khawaja K, Kriege O, Pante SV, Bullinger L, Strand S, Strand D, Theobald M, Kindler T. SIRT1 prevents genotoxic stress induced p53 activation in acute myeloid leukemia. Blood. 2014 Jul 3;124(1):121-33.
4. Yun H, Narayan N, Vohra S, Mupo A, Giotopoulos G, Madrigal P, Sasca D, Lara-Astasio D, Horton SJ, Agrawal-Singh S, Meduri E, Basheer F, Marando L, Gozdecka M, Dovey OM, Castillo-Venzor A, Wang X, Gallipoli P, Müller-Tidow C, Osborne CS, Vassiliou GS, Huntly BJP. Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction. Nature Genetics 2021 Sep 23.
5. Shah V#, Giotopoulos G#, Osaki H#, Meyerhöfer M, Meduri E, Schubert B, Yun H, Horton SJ, Agrawal-Singh S, Haehnel PS, Basheer F, Kühn MWM, Guezguez B, Theobald M, Kindler T, Gallipoli P, Prinjha RK, Huntly BJP*, Sasca D*. Acute resistance to BET inhibitors remodels compensatory remodeling programs via p300 co-activation. *equal contribution and correspondence. Revised manuscript in preparation, pre-print doi: doi.org/10.1101/2022.09.14.507850.
* Shared first authorship; # Co-corresponding authorship