Research line dr P.J. (Pernette) Verschure
Epigenetic transcription regulation and its contribution to a diseased state: State switching in time and space
The Verschure group focuses on epigenetic cell state switching in mammalian cells and its contribution to a diseased state studying (i) breast cancer endocrine therapy resistance development, (ii) UV-induced damage and repair regulation and (iii) epigenetic-based age determination as forensic application. Epigenetic gene regulation is crucial for cellular identity, while allowing changes to environmental cues. The Verschure group aims to understand molecular design principles of epigenetic gene regulation at temporal and spatial/organisational scale. Time-delay, memory, cell-cell variability and robustness are studied as functional performance concepts of epigenetic gene regulation. Computational simulation is used in combination with engineered (synthetic) mammalian cell systems and tools to modulate (trans)genes and the epigenetic state at predefined genomic regions. This approach enables to measure input-output relationships of epigenetic regulation in multiple individual cells in a population. MS2 transcript tagging and single molecule RNA FISH are used as systematic, quantitative measurements of transcription dynamics as function of the epigenetic chromatin state in single living mammalian cells with high precision using advanced microscopy/super-resolution imaging (SIM, 4Pi, PALM/STORM) combined with stochastic modelling. The Verschure research combines results from epigenetic gene (de)regulation with the development of novel tools to predict and monitor treatment responsiveness and chronological age in individuals, setting the scene for personalised systems medicine.
The Verschure group combines five research topics:
- The development of breast cancer endocrine therapy non-responsiveness in the context of a EU H2020 Marie Slodowska-Curie Innovative Training Network project entitled 'EpiPredict' (www.EpiPredict.eu) (PhD student projects of MSc William Beckman, MSc Stefania Astrologo and MSc Maryam Soleimani)
- UV-induced damage and repair processing in the context of an NWO Zon-MW-TOP research project in collaboration with ErasmusMC Rotterdam (PhD student project of MSc, ir. Ilona M. Vuist)
- Design principles of epigenetic gene regulation in living cells (PhD student projects MSc Lisette C.M. Anink-Groenen, ing. Diewertje G.E. Piebes, MSc. Mannus Kempe).
- Development of a forensic-applied epigenetic age determination tool in collaboration with the Netherlands Forensic Institute, prof. Ate Kloosterman and the Co van Ledden Hulsebosch interdisciplinary expertise centre (CLHC) for forensic and medical research (postdoc project Dr. Jana Naue)
- Huntington’s disease development in collaboration with prof. Antoine van Kampen and Dr. Perry Moerland, AMC, UvA.
- Pernette Verschure received (as coordinator) 2.8 M euro funding for the EU H2020 Marie Slodowska-Curie Innovative Training Network project EpiPredict (www.EpiPredict.eu), providing research training for 12 PhD students (3 at SILS, UvA). This effort sets out a new research line following a systems medicine approach to assess how epigenetic reprogramming affects tumour responses to endocrine therapy and predict breast cancer therapy resistance.
- Verschure started collaborating with the NFI and received funding (NCTV, Minesterie van Veiligheid en Justitie) to develop an epigenetic-based age determination forensic tool.
- Verschure and coworkers published 2 papers using engineered mammalian cells and stochastic modelling, showing (i) that the precise relationship between transcript number and cell volume sets transcriptional stochasticity and that mRNA statistics is gene location dependent (Kempe et al. Mol. Biol Cell 2015) and (ii) that chromatin connectivity introduces epigenetic chromatin state switching describing the mechanistic behavior of chromatin epigenetic pattern formation along a single gene (Anink-Groenen et al. Epigenetics Chromatin 2015).
- Verschure and colleagues showed cause and consequence of chromatin contact maps using engineered (lacO/lacR) binding platforms (Wijchers et al. Mol Cell 2016).
- Verschure and coworkers highlighted the consequences of artificial reproduction technologies on the epigenetic profile and its impact on imprinting disorders such as Angelman and Beckwith-Wiedemann syndrome (Hoeijmakers et al. Mol. Reprod. Dev. 2015).
The Masterclass ‘Epigenetics’ for VWO students (class 7-8) 22nd March 2016 organised in collaboration with the Its Academy at Science Park, was a great success. Pernette Verschure gave a key-lecture on the basis of epigenetics, cell identity and its impact for health. Together with Diewertje Piebes (SSB-NOG, SILS) and Stephanie Gessel the VWO students performed handicraft to illustrate nucleosomal chromatin folding and epigenetic marks and a hands-on experiment showing histone acetylation with Western blotting.
dr. P.J. (Pernette) Verschure