Dr. F. Della Ragione coordinates the laboratory of Functional Genomics and Epigenetics at the Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (IGB-CNR), Naples, Italy. She has long-lasting experience in human genetic, epigenetic and epigenomic fields. Since many years, she has been studying molecular mechanisms deregulated in Rett syndrome (RTT), by using genetic and epigenetic approaches and taking advantage of both cellular and mouse models. RTT is a severe neurodevelopmental disease classified as an autism spectrum disorder (ASD) and a chromatin disease, caused by mutations in the epigenetic factor MeCP2.

Early in her career, Dr. F. Della Ragione identified new mutations in MECP2 gene in RTT patients, and contributed to study MeCP2 target genes and genetic modifiers of RTT. She also analyzed epigenetic mechanisms involved in pathogenesis of two other chromatin diseases, ICF and FSHD syndromes. During her post-doc, she developed two novel epigenetic-based strategies for non-invasive prenatal diagnosis of X-chromosome aneuploidies. She also contributed to study the role of DNA methylation in the regulation of plasticity in the mouse developing visual cortex.

In the past years, she highlighted the involvement of oxidative stress in RTT pathogenesis, taking advantage of both patients and murine models of RTT, identifying the oxidative brain damage as a previously unrecognized hallmark feature of RTT in mice, and suggesting a role of MeCP2 in the protection of the brain from oxidative stress.

Furthermore, she dissected molecular mechanisms underlying MeCP2-mediated organization of chromatin architecture in neurons, identifying novel MeCP2 molecular partners involved in this process, as the chromatin remodeler ATRX and ncRNAs, by using sophisticated molecular biology and imaging methodologies (3D DNA/RNA FISH and immuno-RNA FISH), and chromatin/RNA immunoprecipitation techniques.

More recently, she also investigated a feature still unexplored in RTT, represented by the integrity of blood–brain barrier (BBB), providing the first indication of an altered BBB permeability in RTT mouse models

The main research interest of her laboratory is focused on the study of imbalanced sphingolipid metabolism in RTT, its molecular bases and its correction through ad hoc pharmacological treatments. These studies, for which she received dedicated funding, are achieved in cellular and animal RTT models through the use of innovative strategies and genome-wide technologies (e.g.: multi-omic approaches).

With a parallel research project, she is also interested to the identification of novel mutations and/or pathogenetic variants linked to Rett syndrome, through whole exome sequencing of DNA samples from RTT patients without mutations in the known genes and from their parents (trios).

Stroke Causes DNA Methylation at Ncx1 Heart Promoter in the Brain Via DNMT1/MeCP2/REST Epigenetic Complex. Guida N, Serani A, Sanguigno L, Mascolo L, Cuomo O, Fioriniello S, Marano D, Ragione FD, Anzilotti S, Brancaccio P, Molinaro P, Pignataro G, Annunziato L, Formisano L. J Am Heart Assoc. 2024 Mar 19;13(6):e030460. doi: 10.1161/JAHA.123.030460. Epub 2024 Mar 8.

Blood-Brain Barrier Integrity Is Perturbed in a Mecp2-Null Mouse Model of Rett Syndrome. Pepe G, Fioriniello S, Marracino F, Capocci L, Maglione V, D’Esposito M, Di Pardo A, Della Ragione F. Biomolecules. 2023 Mar 28;13(4):606. doi: 10.3390/biom13040606.

The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory. Poondi Krishnan V, Morone B, Toubiana S, Krzak M, Fioriniello S, Della Ragione F, Strazzullo M, Angelini C, Selig S, Matarazzo MR. Genome Res. 2023 Feb;33(2):169-183. doi: 10.1101/gr.276986.122.

Transcriptomic and Epigenomic Landscape in Rett Syndrome. Marano D, Fioriniello S, D’Esposito M, Della Ragione F. Biomolecules. 2021 Jun 30;11(7):967. DOI: 10.3390/biom11070967. (Cover page).

MeCP2 and Major Satellite Forward RNA Cooperate for Pericentric Heterochromatin Organization. Fioriniello S, Csukonyi E, Marano D, Brancaccio A, Madonna M, Zarrillo C, Romano A, Marracino F, Matarazzo MR, D’Esposito M and Della Ragione F. Stem Cell Reports. 2020 Dec 8;15(6):1317-1332. doi: 10.1016/j.stemcr.2020.11.006.

Epigenetic Factors That Control Pericentric Heterochromatin Organization in Mammals. Fioriniello S, Marano D, Fiorillo F, D’Esposito M, Della Ragione F. Genes. 2020 May 28;11(6):E595. DOI: 10.3390/genes11060595.

ATRX contributes to MeCP2-mediated pericentric heterochromatin organization during neural differentiation. Marano D, Fioriniello S, Fiorillo F, Gibbons R, D’Esposito M and Della Ragione F. Int J Mol Sci. 2019 Oct 29;20(21). DOI: 10.3390/ijms20215371. (Cover page).

Glycosphingolipid metabolic reprogramming drives neural differentiation. Russo D, Della Ragione F, Rizzo R, Sugiyama E, Scalabrì F, Hori K, Capasso S, Sticco L, Fioriniello S, De Gregorio R, Granata I, Guarracino MR, Maglione V, Johannes L, Bellenchi GC, Hoshino M, Setou M, D’Esposito M, Luini A, D’Angelo G. EMBO J. 2017 Dec 27. ii: e97674. DOI: 10.15252/embj.201797674

MECP2 a multi-talented modulator of chromatin architecture. Brief Funct Genomics. Della Ragione, F. *, Vacca, M., Fioriniello, S., Pepe, G. and D’Esposito, M. 2016 Nov;15(6):420-431. Epub 2016 Jun 12. DOI: 10.1093/bfgp/elw023

* Corresponding author

Experience-dependent DNA methylation regulates plasticity in the developing visual cortex. Tognini P, Napoli D, Tola J, Silingardi D, Della Ragione F, D’Esposito M, Pizzorusso T. Nat Neurosci. 2015 May 25. DOI: 10.1038/nn.4026.

Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. De Felice C*, Della Ragione F*, Signorini C*, Leoncini S, Pecorelli A, Ciccoli L, Scalabrì F, Marracino F, Madonna M, Belmonte G, Ricceri L, De Filippis B, Laviola G, Valacchi G, Durand T, Galano JM, Oger C, Guy A, Bultel-Poncé V, Guy J, Filosa S, Hayek J, and D’Esposito M. Neurobiol Dis. 2014 Aug;68:66-77. DOI: 10.1016/j.nbd.2014.04.006. Epub 2014 Apr 24.

*Equal contribution

Non-coding RNAs in chromatin disease involving neurological defects. Della Ragione F, Gagliardi M, D’Esposito M, Matarazzo MR. Front Cell Neurosci. 2014 Feb 25;8:54. DOI: 10.3389/fncel.2014.00054

MeCP2 dependent heterochromatin reorganization during neural differentiation of a novel MeCP2-deficient embryonic stem cell reporter line. Bertulat B*, De Bonis ML*, Della Ragione F*, Lehmkuhl A, Milden M, Storm C, Jost KL, Scala S, Hendrich B, D’Esposito M and Cardoso MC. PLoS One. 2012;7(10):e47848. DOI: 10.1371/journal.pone.0047848. Epub 2012 Oct 24.

*Equal contribution

F(4)-neuroprostanes mediate neurological severity in Rett syndrome. Signorini C, De Felice C, Leoncini S, Giardini A, D’Esposito M, Filosa S, Della Ragione F, Rossi M, Pecorelli A, Valacchi G, Ciccoli L and Hayek J. Clin Chim Acta. 2011 Apr 17. DOI: 10.1016/j.cca.2011.04.016

Differential DNA methylation as a tool for noninvasive prenatal diagnosis (NIPD) of X chromosome aneuploidies. Della Ragione F, Mastrovito P, Campanile C, Conti A, Papageorgiou EA, Hultén MA, Patsalis PC, Carter NP, D’Esposito M. J Mol Diagn. 2010 Nov;12(6):797-807. DOI: 10.2353/jmoldx.2010.090199

Epigenetic alteration of microRNAs in DNMT3B-mutated patients of ICF syndrome. Gatto S*, Della Ragione F*, Cimmino A, Strazzullo M, Fabbri M, Mutarelli M, Ferraro L, Weisz A, D’Esposito M, Matarazzo MR. Epigenetics. 2010 Jul 1;5(5):427-43. DOI: 10.4161/epi.5.5.11999

*Equal contribution

Education and Training

• Oct 2009. Specialist Degree “summa cum laude” in Medical Genetics at University of Ferrara.
• Jan 2005. PhD in Advanced Biology at University of Naples “Federico II”.
• Sept 2001. Italian professional certification as Biologist.
• July 2000. MSc degree “summa cum laude” in Biological Sciences at University of Naples “Federico II”.

Research Experience

Nov 2020 – Present. Group leader of the Laboratory of Functional Genomics and Epigenetics at IGB-ABT, studying genetic and epigenetic mechanisms deregulated in Rett syndrome.

Dec 2018 – Present. CNR Technologist (permanent position), Naples, Italy.

Oct 2012 – Nov 2018. CNR Research Scientist (temporary position) at IGB-ABT, Naples, Italy.

Mar 2006 – Sept 2012. Senior Post-Doc fellow at IGB-ABT, Naples.

Nov 2009 – Dec 2009. Stage at BSRC “A. Fleming” Institute, Greece, with a “Short term mobility 2009, CNR” fellowship.

July 2006 – Oct 2009. Medical Genetics School at University of Ferrara, Italy. Research activity at IGB-ABT, Naples, Italy.

May 2005 – June 2005. Telethon Foundation benefit at IGB-ABT, Naples, Italy.

Mar 2004 – Mar 2005. Junior Post-Doc fellow at IGB-ABT, Naples, Italy.

Feb 2004. Telethon Foundation benefit at IGB-ABT, Naples, Italy.

Sept 2002 – Aug 2003. CNR fellow at IGB-ABT, Naples, Italy.

Nov 2001 – Oct 2004. PhD student at University Federico II, Naples, Italy. Research activity at IGB-ABT, Naples.

Mar 2001 and July 2001. Two Telethon Foundation awards at IGB-ABT, Naples, Italy.

Sept 2000 – Sept 2001. Post-degree trainee at IGB-ABT, Naples, Italy.

Mar 1999 – July 2000. Undergraduate student at the Department of Biological Chemistry, University Federico II, Naples, Italy.

Awards

October 2013. Poster prize sponsored by European Association for Cancer Research (EACR) during the FEBS Workshop on “Translating Epigenome into Function: a Next-generation Challenge for Human Disease”. Capri (Naples) ITALY

Research Funding (2016 – Present)

• Fondation Jerome Lejeune Project (2016 – 2019). “Glicosphyngolipids metabolic alterations and pharmacological treatment in animal models of MeCP2 dependent neuropathologies” (Principal investigator).
• PRIN: PROGETTI DI RICERCA DI RILEVANTE INTERESSE NAZIONALE – Bando 2015 (2017 – 2020). “Role of the master epigenetic reader Methyl CpG binding Protein 2 (MeCP2) in gene expression after stroke” (Principal investigator of a Research Unit).
• PON/MISE 2014-2020 FESR F/050011/01-02/X32 (2019 – Present). “Functional Genomics of rare genetic diseases: realization of innovative tools with high diagnostic power” (Co-investigator).
• PON/MISE 2014/2020 Agrifood CAPSULE (2019 – 2022). “Ottimizzazione delle tecniche di allevamento e dei processi produttivi del settore lattiero-caseario bufalino e del vino per la produzione di alimenti funzionali” (Consultant).
• Fondation Jerome Lejeune Project (2021 – 2023). “Pharmacological treatment with sphingosine receptor modulating drugs to correct glycosphingolipid metabolic derangements in Rett syndrome models” (Principal investigator).
• Associazione Italiana Sindrome di Rett (AIRETT) (2022 – Present).”Glycosphingolipid metabolic imbalance in Rett syndrome as a novel target for a drug repositioning-based therapy. (Principal investigator)
• PON/MISE F/310110/05/X5 FORMULAMI (2023 – Present). “FORmulazione di Mangimi di precisione per la creazione di diete personalizzate e prodUzione di prodotti animaLi funzionalizzati, utili nella prevenzione di pAtologie MetabolIche”. (Consultant).
• Telethon Foundation Research Project (2024 – Present). “Sphingolipid metabolic imbalance in murine and hiPSC RTT models: development of a drug repurposing-based therapy”. (Principal investigator)
• Bando a Cascata Partenariato Esteso (2024-2025). “A multiscale integrated approach to the study of the nervous system in health and disease” – MNESYS SPOKE N. 3 Neuronal Homeostasis and brain-environment interaction. “CNR MultidisciplINary adVancEd platform for targeting Neuronal and glal homeosTasis”. (Participant).

 Editorial tasks:

• Epigenetic Diagnosis & Therapy (EDT), Editorial Board Member 2013 – Present
• Solicited reviewer for Clinical Epigenetics
• Frontiers in Molecular Neuroscience, Review Editor 2019 – Present.
• Biomolecules, Guest Editor of the Special Issue “Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways” 2021 – 2022

Teaching activity

• Experience as officially appointed supervisor of undergraduate students.
• Experience as officially appointed supervisor of PhD students.
• Teaching activity for students of the University of Naples Federico II
• Teaching activity for PhD students of the University of Campania “Luigi Vanvitelli”
• Participation to the manifestation of scientific divulgation “Futuro Remoto 2017”