Dr. Cristina Leoni awarded the Best PhD Thesis for the year 2017 from the University of Bern

on February 9, 2018

On occasion of the «GCB Symposium 2018», held on February 01, 2018, at the Department of Chemistry and Biochemistry and the Department of Physiology, University of Bern, the GCB Award for Best PhD Thesis for the year 2017 was conferred on Cristina Leoni, PhD of Science in Biochemistry and Molecular Biology, for her PhD thesis entitled «DNA methylation and hydroxymethylation regulate mast cell proliferation and effector functions». This work has been done in the Molecular Immunology laboratory of Silvia Monticelli.

Cristina is currently continuing working as a scientist in Dr. Silvia Monticelli’s lab, on projects related to her main interest, namely the role of epigenetic modifications in regulating gene expression and immune cell functions. More specifically, she is focusing her attention on the role of DNA-modifying enzymes and DNA modifications in human T lymphocyte responses.

The IRB wishes to congratulate Cristina for her excellent work and this award.

The laureate Cristina Leoni receiving the GCB Award for Best PhD Thesis 2017 from Prof. Dr. Oliver Mühlemann, President of the GCB

PhD Thesis Abstract

Methylation of the 5’ carbon residue of cytosine (5mC) in genomic DNA is a key epigenetic modification which regulates gene expression by recruiting protein involved in gene repression or impairing the binding of transcriptional activators at regulatory regions of genes. 5mC deposition is catalyzed by DNA methyltransferases (DNMTs) enzymes and can be further oxidized by the action of Ten-Eleven-Translocation (TET) enzymes into 5-hydroxymethylcytosine (5hmC) and further oxidized products. While the iterative oxidation of 5mC followed by deamination and DNA repair can result in DNA demethylation, 5mC oxidation can also influence directly gene transcription through the recruitment of specific binding-factors.  Importantly, alteration of DNA methylation and hydroxymethylation landscape as well as mutations affecting DNA-modifying enzymes (most commonly DNMT3A and TET2) are frequently observed in several types of myeloid disorders, including systemic mastocytosis a myeloproliferative neoplasm of mast cells. Mast cells are innate immune cells known to play an important role in modulating immune responses as well as allergic reactions. Although some genetic variants have been associated with the occurrence of mast cells disorders, the molecular mechanisms underlying their pathogenesis remain still largely unknown, and growing evidences suggest that epigenetic processes (including 5mC and 5hmC) could play a role in the pathogenesis of these diseases. In line with this, we found that patients with systemic mastocytosis present low levels of both 5mC and 5hmC as compared to healthy controls (Leoni et al., 2015). We therefore investigated the role of DNA methylation and hydroxymethylation in regulating mast cell biology. First, we found that 5hmC and TET enzymes activity are primarily involved in regulating mast cell differentiation and proliferation (Montagner et al., 2016). Instead, 5mC appeared to be mostly involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo (Leoni et al., 2017). In summary, our work showed that both DNA methylation and hydroxymethylation are important to shape biological and physiological process in mast cells, pointing towards a possible role for these epigenetic modifications in influencing mast cell-related diseases and potentially providing new entry point for therapy for all types of mast cell-related disorders.

Articles

Reduced DNA methylation and hydroxymethylation in patients with systemic mastocytosis

C. Leoni, S. Montagner, L. Deho, R. D’Antuono, G. De Matteis, A. V. Marzano, S. Merante, E. M. Orlandi, R. Zanotti, S. Monticelli – in Eur J Haematol (2015) vol. 95 pp566-75

TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities

S. Montagner, C. Leoni, S. Emming, G. Della Chiara, C. Balestrieri, I. Barozzi, V. Piccolo, S. Togher, M. Ko, A. Rao, G. Natoli, S. Monticelli – in Cell Rep (2016) vol. 15 pp1566-79

Dnmt3a restrains mast cell inflammatory responses

C. Leoni, S. Montagner, A. Rinaldi, F. Bertoni, S. Polletti, C. Balestrieri, S. Monticelli – in Proc Natl Acad Sci U S A (2017) vol. 114 ppE1490-E1499

Link to Graduate School for Cellular and Biomedical Sciences (GCB): http://www.gcb.unibe.ch/research/awards/index_eng.html