The Past...EVOLUTION, EPIGENETICS AND POST-TRANSCRIPTIONAL REGULATION OF human XYqPAR-genes

Since the beginning of my carrier, I have been fascinated by the biology of mammalian sex chromosomes-linked genes for their peculiar evolution, together with the epigenetic mechanisms that regulate their expression, both in physiology and pathology. Following this path, I collaborated to the characterization of two human XY-homology regions; I also contributed to study allelic-expression profile of X-linked and imprinted genes in specific human pathologies, characterized by epigenetic impairments, such as ICF syndrome, Rett syndrome (RTT) and hyper-homocysteinemia.

& The Present...MECP2, RETT SYNDROME and X CHROMOSOME INACTIVATION

• As soon as I met some patients with RTT, the X-linked gene MECP2 completely captured me. RTT is a severe and rare neurodevelopmental disorder, belonging to the sphere of autistic disorders. It is mainly caused by heterozygous mutations in the MECP2 gene that encodes an epigenetic regulator. Patients with RTT still waits for a cure. In the field of human genetics, I described the first molecular diagnosis of MECP2 in Italian and UK patients with RTT. We were the first group to look for additional genetic factor that could be involved in the pathogenesis of RTT.
• In the last few years, by using a combination of genetic, molecular, cellular and bioinformatics approaches, we investigated mechanisms deregulated in a mouse model of the human disease, focusing on a developmental window taking place long time before RTT symptoms onset. An ongoing project aims to select compounds effective in rescuing the precocious morphological and molecular RTT phenotypes we found in embryonic primary cortical neurons from Mecp2 null mice.
• Moreover, my team is currently addressing Mecp2 as a direct target for therapy of RTT. Indeed, because of X chromosome inactivation process (XCI), one allele of the gene is randomly silenced in somatic female cells and could be used as a functional backup to rescue the disease when reactivated. In order to counteract the epigenetic features of the Mecp2 silent copy, a reporter cell-based automated screening of small molecules has been developed in the lab in collaboration with dr. Laura Casalino. To this aim, a new Mecp2 transgenic reporter line has been generated with the support of IGB mouse modeling facility. In parallel, we are tracing Mecp2 inactivation profiles during mouse development, as the XCI might contribute to clinical variability of RTT symptoms.

GUEST EDITOR

1. Matteo Gasparotto, Elena Dall'Ara, Marcella Vacca* and Francesco Filippini. VAMP7j: A Splice Variant of Human VAMP7 That Modulates Neurite Outgrowth by Regulating L1CAM Transport to the Plasma Membrane. IJMS (2023) Online ISSN: 1422-0067
   
2. Irene Righetto, Matteo Gasparotto, Laura Casalino, Marcella Vacca* and Francesco Filippini. Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis. Biomolecules (2023) 13, no. 1: 169. https://doi.org/10.3390/biom13010169
3. Matteo Gasparotto,Yi-Shin Lee, Alessandra Palazzi, Marcella Vacca* and Francesco Filippini. Nuclear and Cytoplasmatic Players in Mitochondria-Related CNS Disorders: Chromatin Modifications and Subcellular Trafficking. Biomolecules (2022), 12, 625. https://doi.org/10.3390/biom12050625
4. Della Ragione F, Vacca M, Fioriniello S, Pepe G, D'Esposito M. MECP2, a multi-talented modulator of chromatin architecture. Briefings in functional genomics (2016) 15(6):420-431. ISSN: 2041-264
5. Vacca M*, Della Ragione F, Scalabrì F, D'Esposito M. X inactivation and reactivation in X-linked diseases. Seminars in cell & developmental biology (2016) 56:78-87. ISSN: 1084-9521
6. Vacca M, Tripathi KP, Speranza L, Aiese Cigliano R, Scalabrì F, Marracino F, Madonna M, Sanseverino W, Perrone-Capano C, Guarracino MR, D'Esposito M. Effects of Mecp2 loss of function in embryonic cortical neurons: a bioinformatics strategy to sort out non-neuronal cells variability from transcriptome profiling. BMC bioinformatics (2016) 17 Suppl 2:14. ISSN: 1471-2105
7. Kumar Parijat Tripathi, Maurizio D'Esposito, Mario R Guarracino, Marcella Vacca*. Deep Insights Into Mecp2-Driven Transcriptional (De)Regulation At Embryonic Developmental Stage Through RNA-Seq Data Analysis. EMBNET JOURNAL (2015) vol. 21, ISSN: 2226-6089
8. Vacca M, Albania L, Della Ragione F, Carpi A, Rossi V, Strazzullo M, De Franceschi N, Rossetto O, Filippini F, D'Esposito M. Alternative splicing of the human gene SYBL1 modulates protein domain architecture of Longin VAMP7/TI-VAMP, showing both non-SNARE and synaptobrevin-like isoforms. BMC molecular biology. (2011) 12:26. ISSN: 1471-2199
9. Matarazzo MR, De Bonis ML, Vacca M, Della Ragione F, D'Esposito M. Lessons from two human chromatin diseases, ICF syndrome and Rett syndrome. The international journal of biochemistry & cell biology (2009) 41(1):117-26. ISSN: 1357-2725
10. Martinez-Arca S, Rudge R, Vacca M, Raposo G, Camonis J, Proux-Gillardeaux V, Daviet L, Formstecher E, Hamburger A, Filippini F, D'Esposito M, Galli T. A dual  mechanism controlling the localization and function of exocytic v-SNAREs. Proceedings of the National Academy of Sciences of the United States of America. (2003) 100(15):9011-6. ISSN: 0027-8424
11. Rossi V, Banfield DK, Vacca M, Dietrich LE, Ungermann C, D'Esposito M, Galli T, Filippini F. Longins and their longin domains: regulated SNAREs and multifunctional SNARE regulators. Trends in biochemical sciences (2004) 29(12):682-8. ISSN: 0968-0004
12. Ingrosso D, Cimmino A, Perna AF, Masella L, De Santo NG, De Bonis ML, Vacca M, D'Esposito M, D'Urso M, Galletti P, Zappia V. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet (London, England 2003) 361(9370):1693-9. ISSN: 0140-6736
13. Nicolao P, Carella M, Giometto B, Tavolato B, Cattin R, Giovannucci-Uzielli ML, Vacca M, Della Regione F, Piva S, Bortoluzzi S, Gasparini P. DHPLC analysis of the MECP2 gene in Italian Rett patients. Human mutation. (2001) 18(2):132-40. ISSN: 1059-7794
14. Vacca M, Filippini F, Budillon A, Rossi V, Mercadante G, Manzati E, Gualandi F, Bigoni S, Trabanelli C, Pini G, Calzolari E, Ferlini A, Meloni I, Hayek G, Zappella M, Renieri A, D'Urso M, D'Esposito M, MacDonald F, Kerr A, Dhanjal S, Hultén M. Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females. Journal of molecular medicine (Berlin, Germany 2001) 78(11):648-55. ISSN: 0946-2716

 *corresponding author

EDUCATION

• 2003:    PhD in Neurosciences (Audioverbal communication physiology) at the Faculty of Medicine of the University of Naples- Federico II-, defending the thesis “Molecular and Physiological analysis of Rett Syndrome” (tutor, prof. Elio Marciano).
• 1998:    Bachelor degree cum laude in Biological Sciences at the University of Naples (Italy), defending the thesis in Molecular Biology “Structural and evolutionary analysis of the human homology region Xq21.3/Yp11.1” (tutor, dr. Michele D’Urso).

RESEARCH APPOINTMENTS

• 2021- present: coordinator of IGB Informatics Core, responsible of IGB website.
• 2013-2016: coordinator of OBiLab (Open Bioinformatics Laboratory, http://www.igb.cnr.it/obilab)
• 2012 – present: Research Scientist at the IGB-ABT, CNR-Naples (Italy)
• 2006-2007: Regional Center for Education (GEAR) -University of Naples “Federico II”- fellowship
• 2004-2006: University of Padua (Italy) -Postdoctoral fellowship in Molecular and Cellular Biology
• 2004: INSERM Institute, Dept. of Membrane trafficking and Neuronal Plasticity, Paris (France)- Visiting scientist
• 2004: IGB-ABT, CNR-Naples (Italy)- CNR-Co.Co.Co. and Telethon Foundation fellowship
• 2002-2003: IGB-ABT, CNR-Naples (Italy)- Telethon Foundation fellowship
• 1999-2002: Faculty of Medicine - University of Naples “Federico II”- PhD student in Neurosciences
• 1999-2000: IGB-ABT, CNR-Naples (Italy)- Post−degree training

FUNDING

• 2019-2022: Associazione Italiana Sindrome di Rett (AIR)- Bando 2018 “Toward the pharmacological reactivation of Mecp2: developing new pre-clinical tools for the Rett syndrome” (Co-PI)
• 2017-2019: Associazione Italiana Sindrome di Rett (AIR)- Bando 2016 “Reactivation of the dormant wild-type allele of Mecp2 as a therapy for Rett syndrome: screening of epigenetic compounds” (PI)
• 2017-2019: Innovative Life sCience PhD program in South Italy-INCIPIT” co-funded by EU-HORIZON 2020/Marie Sklodowska Curie Action (Participant Unit, PhD fellow- dr. Yi-Shin Lee)- http://www.igb.cnr.it/wpincipit/index.php/supervisor-2017
• 2014-2015: Associazione Italiana Sindrome di Rett (AIR)- Bando 2014 “Utilizzo di due nuove potenti armi farmacologiche per sconfiggere i difetti neuronali della Sindrome di Rett” (Participant Unit)

TRAINING, TEACHING & TUTORING

• 2021-2022: Undergraduate student supervisor (Alessandra Palazzi)-"Contributo allelico all’espressione del gene Mecp2 durante lo sviluppo del cervello murino"
• 2019-2020: Undergraduate student supervisor (Antonietta Esposito)- “Caratterizzazione fenotipica e molecolare di una linea transgenica reporter per tracciare in vivo l'espressione allelica del gene X-linked Mecp2”
• 2018-2020: Lecturer for PhD students (PhD Program in Biomolecular Sciences - Università degli Studi della Campania Luigi Vanvitelli- “X inactivation and reactivation in X-linked diseases”
• 2017-2020: INCIPIT-PhD student supervisor (dr. Yi-Shin Lee)- “Toward the reactivation of the dormant allele of MECP2 as a therapy for Rett syndrome”
• 2017-2018: Undergraduate student supervisor (Mariangela Manno)- “Riattivazione dell’allele silente del gene Mecp2 come terapia per la sindrome di Rett: generazione di una nuova linea transgenica reporter”
• 2010-2011: Supervisor PON Project C1-FSE-2010-2663
• 2009-2010: Supervisor, PON Project " ob. B azione B1"
• 2008-2011: Coordinator of the Regional Project PISA-OCSE
• 2007-2012: Full-time teacher in the secondary school (Naples, Italy).

EVALUATION COMMITTEES

• 2018:    Member of the Scientific committee REPRISE (MUR).
• 2017 a:   Evaluation Committee President for a public selection of Early Stage Researchers (INCIPIT project- “Unravelling genetic modifiers of Incontinentia Pigmenti and their role in the NF-kappaB pathway”)
• b:    Evaluation Committee member for a public selection of Early Stage Researchers (INCIPIT project- "Reactivation of the dormant wild type allele MECP2 as a therapy for Rett syndrome: screening of epigenetic compounds")
• c:    Member of the Scientific committee at the 3rd edition of the Bringing Maths to Life Workshop, held in Naples on 7-9 June 2017 (http://www.bmtl.it).
• 2016:    Editorial board member “Dynamics of Mathematical Models in Biology-Bringing Mathematics to Life” book

AD HOC REVIEWER

Solicited reviewer for International Journals of Springer.

OUTREACH & DISSEMINATION

• 2021:  Futuro Remoto 2021-Transizioni-La biomedicina verso il futuro- Rosalind Franklin: “la Foto 51” (lecturer and trainer)
• 2019: The week of science- 5th edition-Convitto Nazionale Vittorio Emanuele II di Napoli (Coordinator and trainer)
• 2018: 32° Edizione di divulgazione scientifica, Futuro Remoto (trainer)
• 2016- present: co-author of VIVIRETT  official magazine of the Associazione Italiana Sindrome di Rett