Overview

«The Waltz of the polipeptides», by Mara G. Haseltine, 2003 

For decades, eukaryotic gene expression was thought to be controlled primarily at the transcriptional level. This view is rapidly giving way to a richer picture in which post-transcriptional networks - composed of RNA-binding proteins, non-coding RNAs, and dynamic RNA modifications - critically shape the proteome by regulating mRNA stability, localisation, and access to translation.

Our laboratory operates squarely within this RNA-centric landscape. We are rewiring transcriptomes to rescue the molecular faults that trigger neurodegeneration in some monogenic diseases and to unlock the stalled differentiation programmes of neural tumours. In doing so, we are pursuing both a deeper understanding of RNA biology and new therapeutic avenues for currently intractable diseases.

Research directions

We approach translation as a tractable, disease‑relevant control point. By engineering cis‑elements such as Kozak motifs and perturbing trans‑acting readers of RNA modifications, we modulate gene expression to drive terminal differentiation in neural tumours and to correct protein dosage in triplosensitive or haploinsufficient disorders.

  • Identification of Targets for Terminal Differentiation of Neural Tumors
    Neuroblastoma - a neural crest-derived malignancy and the leading cause of cancer-related death in childhood - arises when sympathetic progenitors fail to complete their maturation into ganglion neurons or chromaffin cells. Glioblastoma, in contrast, often originates from radial‑glia‑like neural stem cells in the subventricular zone; early driver mutations derail their differentiation programme, yielding a reservoir of poorly differentiated, highly proliferative cells that infiltrate the brain parenchyma. Using single-cell transcriptomics and pooled high-throughput genetic screens, we are systematically identifying and testing interventions capable of restoring terminal differentiation in these therapy-resistant tumours.
  • Promoting Terminal Differentiation by Suppressing m6A Signalling
    A flagship line of investigation targets the YTHDF family of m6A-reading RNA-binding proteins as potential differentiation switches in neural tumours. Using customised small molecule probes and CRISPR-based genome editing, we are imposing deep, selective silencing of YTHDF gene expression and tracking the downstream consequences - both in vitro and in vivo - on tumour cell identity and growth.
  • Base Editing–Driven Translational Reprogramming for Dose‑Sensitive Gene Disorders
    We have established proof‑of‑principle that single‑nucleotide edits within Kozak motifs allow precise tuning of the translational output of selected human mRNAs. Building on this result, we are deploying the strategy to rescue cellular phenotypes in triplosensitive and haploinsufficient disorders. In parallel, we are systematically charting the sequence determinants that dictate Kozak efficiency in human cells, with the goal of creating a predictive framework for the control of translation initiation.
  • Fine-tuning the Translation of Therapeutic mRNAs
    Therapeutic mRNAs must be translated at rates that maintain the correct folding and activity of their protein products. We tune these kinetics by (i) embedding tailored cis-regulatory elements and (ii) conjugating transcripts to ribosome-recruiting proteins that increase initiation efficiency. A major application of this platform is the optimisation of base-editor mRNA delivery and expression in neural tissues.

Group members

  • Alessandro Quattrone, PI
  • Georgios Poulentzas, PhD student
  • Jacopo Vigna, postdoc
  • Francesca Broso, postdoc
  • Riccardo Gilmozzi, predoc
  • Angelo Guarniero, postdoc
  • Maria Corinna Diener, predoc
  • Denise Sighel, postdoc
  • Emanuele Rosatti, PhD student
  • Giorgia Zappacosta, PhD student
  • Alberto Raoss, PhD student
  • Samuele Sanniti, PhD student
  • Fabio Baranzoni, predoc
  • Elisabetta Rossi, predoc
  • Sofia Eminente, predoc
  • Anna Veronese, predoc
  • Giorgio Baldessari, predoc
  • Riccardo Giaquinta, PhD student

Some recent publications

Destefanis E, Sighel D, Dalfovo D, Gilmozzi R, Broso F, Cappannini A, Bujnicki JM, Romanel A, Dassi E, Quattrone A. The three YTHDF paralogs and VIRMA are strong cross‑histotype tumour driver candidates among m6A core genes. NAR Cancer  2024;6(4):zcae040. doi:10.1093/narcan/zcae040.

Sighel D, Destefanis E, Quattrone A. Therapeutic strategies to target the epitranscriptomic machinery. Curr Opin Genet Dev  2024;87:102230. doi:10.1016/j.gde.2024.102230.

Cocchi S, Greco V, Sidarovich V, Vigna J, Broso F, Corallo D, Zasso J, Re A, Rosatti EF, Longhi S, Defant A, Ladu F, Sanna V, Adami V, D’Agostino VG, Sturlese M, Sechi M, Aveic S, Mancini I, Sighel D, Quattrone A. EGCG disrupts the LIN28B/let‑7 interaction and reduces neuroblastoma aggressiveness. Int J Mol Sci  2024;25(9):4795. doi:10.3390/ijms25094795.

Cazzanelli G, Dalle Vedove A, Spagnolli G, Terruzzi L, Colasurdo E, Boldrini A, Patsilinakos A, Sturlese M, Grottesi A, Biasini E, Provenzani A, Quattrone A, Lolli G. Pliability in the m^6A‑binding region extends druggability of YTH domains. J Chem Inf Model  2024;64(5):1682‑1690. doi:10.1021/acs.jcim.4c00051.

Broso F, Gatto P, Sidarovich V, Ambrosini C, De Sanctis V, Bertorelli R, Zaccheroni E, Ricci B, Destefanis E, Longhi S, Sebastiani E, Tebaldi T, Adami V, Quattrone A. α‑1‑Adrenergic antagonists sensitise neuroblastoma to therapeutic differentiation. Cancer Res  2023;83(16):2733‑2749. doi:10.1158/0008‑5472.CAN‑22‑1913.

Micaelli M, Dalle Vedove A, Cerofolini L, Vigna J, Sighel D, Zaccara S, Bonomo I, Poulentzas G, Rosatti EF, Cazzanelli G, Alunno L, Belli R, Peroni D, Dassi E, Murakami S, Jaffrey SR, Fragai M, Mancini I, Lolli G, Quattrone A*, Provenzani A*. Small‑molecule ebselen binds to YTHDF proteins, interfering with m^6A‑RNA recognition. ACS Pharmacol Transl Sci  2022;5(10):872‑891. doi:10.1021/acsptsci.2c00008.

Ambrosini C, Destefanis E, Kheir E, Broso F, Alessandrini F, Longhi S, Battisti N, Pesce I, Dassi E, Petris G, Cereseto A, Quattrone A. Translational enhancement by base editing of the Kozak sequence rescues haploinsufficiency. Nucleic Acids Res  2022;50(18):10756‑10771. doi:10.1093/nar/gkac799.

Aiello G, Sabino C, Pernici D, Audano M, Antonica F, Gianesello M, Ballabio C, Quattrone A, Mitro N, Romanel A, Soldano A, Tiberi L. Transient rapamycin treatment during development extends lifespan in mice and flies. EMBO Rep  2022;23(9):e55299. doi:10.15252/embr.202255299.

Licata NV, Cristofani R, Salomonsson S, Wilson KM, Kempthorne L, Vaizoglu D, D’Agostino VG, Pollini D, Loffredo R, Pancher M, Adami V, Bellosta P, Ratti A, Viero G, Quattrone A, Isaacs AM, Poletti A, Provenzani A. C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation. EMBO J  2022;41(1):e105026. doi:10.15252/embj.2020105026.

Ambrosini C, Garilli F, Quattrone A. Reprogramming translation for gene therapy. Prog Mol Biol Transl Sci  2021;182:439‑476. doi:10.1016/bs.pmbts.2021.01.028.

Simone R, Javad F, Emmett W, Wilkins OG, Almeida FL, Barahona‑Torres N, Zareba‑Paslawska J, Ehteramyan M, Zuccotti P, Modelska A, Siva K, Virdi GS, Mitchell JS, Harley J, Kay VA, Hondhamuni G, Trabzuni D, Ryten M, Wray S, Preza E, Kia DA, Pittman A, Ferrari R, Manzoni C, Lees A, Hardy JA, Denti MA, Quattrone A, Patani R, Svenningsson P, Warner TT, Plagnol V, Ule J, de Silva R. MIR‑NATs repress MAPT translation and aid proteostasis in neurodegeneration. Nature  2021;594:117‑123. doi:10.1038/s41586‑021‑03556‑6.

Sighel D, Notarangelo M, Aibara S, Re A, Ricci G, Guida M, Soldano A, Adami V, Ambrosini C, Broso F, Rosatti EF, Longhi S, Buccarelli M, D’Alessandris QG, Giannetti S, Pacioni S, Ricci‑Vitiani L, Rorbach J, Pallini R, Roulland S, Amunts A, Mancini I, Modelska A, Quattrone A. Inhibition of mitochondrial translation suppresses glioblastoma stem‑cell growth. Cell Rep  2021;35(4):109024. doi:10.1016/j.celrep.2021.109024.

Minati L, Firrito C, Del Piano A, Peretti A, Sidoli S, Peroni D, Belli R, Gandolfi F, Romanel A, Bernabo P, Zasso J, Quattrone A, Guella G, Lauria F, Viero G, Clamer M. One‑shot analysis of translated mammalian lncRNAs with AHARIBO. eLife 2021;10:e59303. doi:10.7554/eLife.59303.

Worpenberg L, Paolantoni C, Longhi S, Mulorz MM, Lence T, Wessels HH, Dassi E, Aiello G, Sutandy FXR, Scheibe M, Edupuganti RR, Busch A, Möckel MM, Vermeulen M, Butter F, König J, Notarangelo M, Ohler U, Dieterich C, Quattrone A*, Soldano A*, Roignant JY*. Ythdf is an N^6‑methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila. EMBO J  2021;40(4):e104975. doi:10.15252/embj.2020104975.

*=co-last authors