Lorenzo Chiariotti
Professor of General Pathology at University of Naples “Federico II” where he and his research group investigate the DNA methylation machinery in brain tumor, rare diseases and during cells development.
He is an expert in exploring epigenetics and epigenomics in cancer and neurodevelopmental diseases using second and third generation NGS technologies. Moreover, he studies the involvement of epigenetic mechanisms in the prediction and prevention of X-linked disease in heterozygous females (Fabry disease) and, for these diseases, he is endorsed by Takeda International for the screening of candidate patients. Finally, his research line is focused on epigenetic remodeling (DNA methylation and hydroxymethylation) during neuronal differentiation of stem cells.
Since 2018, he is Principal Investigator at CEINGE for projects in collaboration with Sanofi and Takeda Shire and head of the diagnostic unit "Molecular and Epigenetic Markers in brain tumors" accredited by the Joint Commission International, at CEINGE, per il DAI di Medicina di Laboratorio e Trasfusionale, Azienda Ospedaliera Federico II.
- Fabry disease is a X-linked genetic disorder affecting males, nonetheless women are not just carriers. More than 50% of female carrying mutation develop from mild to severe clinical manifestations. This was quite unexpected because in X-recessive disorders generally female carriers are unaffected. The major aim of this project is to understand why many female carriers are clinically affected and, possibly, to predict disease onset. We hypotesize that epigenetic mechanisms underlie this phenomenon. We plan both to use state of the art epigenomic methodologies and to set up novel advanced molecular methods aimed to in depth investigate the complex mechanisms of unbalanced inactivation of X-linked genes. A web-based database dedicated to carrier women will be generated. The early identification of Fabry female carriers who will develop disease is particularly relevant. Timely substitutive enzymatic therapy is possible but, to date, limited to male carriers. This therapy could be extended to female carriers predicted to develop the disease
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Brain tumors are very heterogeneous and a correct classification and prediction of response to therapy is particularly complex. In collaboration with the research and diagnostic units from Basilea, we evaluate the methylation state of key genes thanks to the methylome analysis (EPIC array). With this method, we are able also to define the copy number variation, identifying duplication or deletion of specific chromosome regions or specific genes. Moreover, we are able to profile the methylome of each patients respect to worldwide tumor database (including TCGA) and visualize this classification on UMAP plot. We are now transferring these investigations to Nanoporetech platform in order to obtain results in extremely faster times. We are also extending methylome-based analyses to study and to predict response to therapies in neuroendocrine tumor (NET), to date never analyzed with methylome.
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We have recently demonstrated that DNA methylation trajectories follow a highly dynamic path during neuronal differentiation and perfectly orchestrated at the level of cell populations despite the apparent stochasticity that we observe in individual cells. Investigations at single molecule and single cell level, obtained through ultradeep methylation analysis, are opening new horizons in understanding how methylation profiles are sculpted through continuous remodeling of the methylation and hydroxymethylation state of each CpG site.
- Rosa Della Monica, research contract CEINGE
- Linda De Risi, research grant
- Mariella Cuomo, PhD student
- Davide Costabile, Student
- Michela Buonaiuto, Student
- Cuomo M, Keller S, Punzo D, Nuzzo T, Affinito O, Coretti L, Carella M, de Rosa V, Florio E, Boscia F, Avvedimento VE, Cocozza S, Errico F, Usiello A, and Chiariotti L. Selective demethylation of two CpG sites causes postnatal activation of the Dao gene and consequent removal of D-serine within the mouse cerebellum. Springer Nature. Clin Epigenetics. 2019 Oct 28;11(1):149. doi: 10.1186/s13148-019-0732-z.
- Keller S, Punzo D, Cuomo M, Affinito O, Coretti L, Sacchi S, Florio E, Lembo F, Carella M, Copetti M, Cocozza S, Balu DT, Errico F, Usiello A, and Chiariotti L. DNA methylation landscape of the genes regulating D-serine and D-aspartate metabolism in post-mortem brain from controls and subjects with schizophrenia. Nature Publishing Group Sci Rep. 2018 Jul 5;8(1):10163. doi: 10.1038/s41598-018-28332-x.
- Florio E, Keller S, Coretti L, Affinito O, Scala G, Errico F, Fico A, Boscia F, Sisalli MJ, Reccia MG, Miele G, Monticelli A, Scorziello A, Lembo F, Colucci-D'Amato L, Minchiotti G, Avvedimento VE, Usiello A, Cocozza S, Chiariotti L.* Tracking the evolution of epialleles during neural differentiation and brain development: D-Aspartate oxidase as a model gene. Epigenetics. 2016 – epub- 2017 Jan 2;12(1):41-54.
- Angrisano T, Sacchetti S, Natale F, Cerrato A, Pero R, Keller S, Peluso S, Perillo B, Avvedimento VE, Fusco A, Bruni CB, Lembo F, Santoro M, and Chiariotti L.** Chromatin and DNA methylation dynamics during retinoic acid-induced RET gene transcriptional activation in neuroblastoma cells. Nucleic Acids Res. 2011 Mar;39(6):1993-2006.
- Keller S, Sarchiapone M, Zarrilli F, Videtic A, Ferraro A, Carli V, Sacchetti S, Lembo F, Angiolillo A, Jovanovic N, Pisanti F, Tomaiuolo R, Monticelli A, Balazic J, Roy A, Marusic A, Cocozza S, Fusco A, Bruni CB, Castaldo G, and Chiariotti L.** Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch. Gen. Psychiatry. 2010 Mar;67(3):258-67. ** corresponding author;