Overview

Decoding the epigenetic landscape is essential to understanding how the brain develops, learns, and functions—and how these processes fail in disease. Our laboratory investigates the epigenetic basis - how chromatin remodeling, histone modifications, and non-coding RNAs (ncRNAs) orchestrate complex brain functions - aiming at identifying molecular switches that can be targeted during the earliest stages of pathology. We study two main paradigms of genetic disorders affecting the central nervous system:
    •    a neurodevelopmental paradigm: Autism Spectrum Disorders (ASD)
    •    a neurodegenerative paradigm: Huntington’s Disease (HD)

Research directions

1. SINEUP RNAs: a novel platform for treating haploinsufficiency in Autism Spectrum Disorder (ASD)

Funded by: Simons Foundation Autism Research Initiative- Genomics of ASD: Pathways to Biological Convergence and Genetic Therapies, MUR_PRIN PNRR, Fondazione Italiana Autismo, and University POC call “Road to Market 2025”   

Autism Spectrum Disorders (ASD) represent a highly heterogeneous group of conditions with a strong genetic component. Most ASD-associated mutations are de novo and lead to reduced protein expression or function (haploinsufficiency). Since typically only one allele is affected, a promising therapeutic strategy is to enhance the expression of the unaffected allele, thereby restoring physiological protein levels.

In this context, we exploit the modularity of SINEUPs, a class of non-coding RNAs capable of selectively enhancing translation of target mRNAs without altering their transcript abundance. In a recent study, our lab generated synthetic SINEUP molecules targeting the Chromodomain helicase DNA binding protein (CHD8), one of the most prominent ASD risk factors. Using SINEUP-CHD8, we successfully increased endogenous CHD8 protein levels in human cells, patient-derived fibroblasts, and zebrafish models. The newly produced protein is fully functional and rescues molecular phenotypes associated with CHD8 suppression.

Building on these promising results, we aim to develop a proof-of-concept for RNA-based therapies targeting haploinsufficiency:

• Evaluate the efficacy of SINEUP-Chd8 in rescuing phenotypes associated with Chd8 repression in vivo in a murine preclinical model.
• Extend the SINEUP approach to additional ASD risk genes associated with haploinsufficiency (ADNP, DYRK1A, GRIN2B, SCN2A, STXBP1, SYNGAP1), using both patient-derived iPSCs and CRISPR-Cas9 edited models.
• Evaluate the ability of SINEUPs to restore functional phenotypes in differentiated neurons, including gene expression profiling and correction of transcriptional alterations. For the most promising SINEUPs, we will further investigate mutation-specific functional phenotypes.
• Investigate the therapeutic potential of SINEUPs in CHD2 haploinsufficiency, a clinically relevant disorder characterized by epilepsy, autism, and intellectual disability. Studies will combine in vitro analyses of transcriptional, epigenetic, proteomic, and functional alterations with in vivo assessment of behavioral and neurophysiological rescue in a Chd2 haploinsufficient mouse model.

2. Telomere dysfunction in Autism Spectrum Disorder

Telomeres, specialized structures that “protect” the ends of eukaryotic chromosomes, play a crucial role in DNA replication and in maintaining genome integrity. Variations in telomere length (TL) or integrity are clearly associated with pathological processes—not only with various forms of cancer, but also with neuropsychiatric disorders. Notably, recent studies have reported alterations in TL in patients with ASD.

Telomere integrity is regulated by TERRA, a class of non-coding RNAs (ncRNAs) transcribed from subtelomeric regions and extending into telomeric sequences. TERRA abundance is tightly linked to telomere stability and, consequently, to chromosomal integrity. Of particular interest are chromatin regulators belonging to the chromodomain helicase DNA-binding protein family (CHD8, CHD2, CHD1, CHD3), all of which are relevant ASD risk factors and are known to interact with TERRA.

Together, these observations suggest a previously underexplored biological aspect in ASD: a potential functional interplay between TERRA, telomeres, and ASD risk factors. Dysregulation of this network may be associated with altered telomere length and compromised genomic integrity—processes that are relevant to ASD and may open new avenues for therapeutic intervention.

3. Genetic approaches to Huntington’s Disease: overlooked phenotypes and possible new disease modifiers.

This autosomal dominant inherited disorder is caused by the expansion of CAG trinucleotide repeats in exon 1 of the HTT gene. The pathological process is primarily associated with the progressive degeneration of striatal and cortical neurons, ultimately leading to patient death.

The Enteric Nervous System (ENS) in Huntington’s Disease. Funded by the European Huntington’s Disease Network (EHDN).
While central nervous system phenotypes in Huntington’s Disease (HD) are well documented, a range of highly debilitating peripheral symptoms—such as unintentional weight loss and gastrointestinal (GI) dysfunction—remain less well characterized, despite their significant impact on patients’ quality of life. The enteric nervous system (ENS), composed of more than a dozen different neuronal subtypes, regulates key gastrointestinal functions including motility, secretion, digestion, and peristalsis. Alterations in ENS function can lead to GI dysfunctions, including dysphagia, which is associated with an increased risk of pneumonia—often a fatal complication in HD patients. In this study, we aim to characterize gastrointestinal (GI) alterations associated with dysfunction of the enteric nervous system (ENS), using the zQ175 transgenic mouse model. Specifically, we will focus on:

• Providing a comprehensive anatomical characterization of potential alterations in the enteric nervous system (ENS);
• Assess gastrointestinal (GI) function;
• Perform single-cell analyses to characterize transcriptional alterations in enteric neurons and glial cells

Circular RNA (circRNA) alterations in the pathogenesis of Huntington’s Disease (HD).

The regulation of alternative splicing is not only crucial for generating the repertoire of RNA isoforms encoding proteins essential for the proper maintenance of cellular functions—particularly in neurons—but also for the biogenesis of circular RNAs (circRNAs). These non-coding RNAs, unusually resistant to degradation, are produced through back-splicing, leading to exon circularization and are highly enriched in neurons. In recent years, their importance as regulators of cellular physiology, development, and disease has become increasingly evident.

• Our laboratory identified and experimentally validated the first circular RNA derived from the HTT locus, termed circHTT (2,3,4,5,6). circHTT is enriched in the central nervous system and is conserved across multiple mammalian species . Its circular nature was validated using divergent primers, sequencing, and RNase R treatment. circHTT/circHtt expression increases significantly with the expansion of CAG repeats, both in terminally differentiated neurons and across different brain regions in various HD mouse models. Our aim is to characterize the temporal and spatial dynamics of circHttexpression and to further investigate its cellular and molecular functions in the nervous system, as well as its potential relevance in the pathophysiology of Huntington’s Disease. Funded by the Hereditary Disease Foundation (HDF), the Telethon foundation, RAPID (MUR_PNRR_M4C2_Inv 1.4_CN_BaC_CN RNA & GT_Spoke 3 IIT) , European Molecular Biology Organization (EMBO postdoctoral fellowship to Jasmin Morandell, ALTF 897-2021) and Unione Europea (MSCA postdoctoral fellowship to Jasmin Morandell, GA n° 101062297 — BrainCircHD).

• Complementing our studies, we analyze blood samples from Huntington’s disease patients and healthy controls to investigate systemic transcriptomic, splicing and back-splicing changes. Our goal is to characterize molecular alterations across different disease stages and identify potential sex-specific differences. Concurrently, we profile and quantify circRNAs to evaluate their potential as robust, blood-based biomarkers. Funded by the Huntington’s Disease Society of America.

Group members

• Marta Biagioli, Ph.D., Principal Investigator
• Jasmin Morandell, Ph.D., MSCA postdoctoral fellow (GA n° 101062297 — BrainCircHD, by the European Union)
• Filomena Grazia Alvino, postdoctoral fellow
• Stefania Santarelli, PhD student in Biomolecular Sciences (UNITN)
• Sara Vinciguerra, research assistant
• Lorenzo Milesi, research assistant
• Arianna Boscato, research assistant
• Kseniya Asadchaya, research assistant
• Giorgia Catenacci, Master’s student in Cellular and Molecular Biotechnologies (UNITN)
• Sara Bortolotto, Master’s student in Cellular and Molecular Biotechnologies (UNITN)

Grants

	University of Trento - Bridge Fund - 5x1000 Fundraising Campaign 2022 -Road to Market Call 2025 https://www.unitn.it/
	Simons Foundation Autism Research Initiative - SFARI https://www.sfari.org/
	European Commission Horizon Europe-Marie Skłodowska-Curie Actions (MSCA) https://ec.europa.eu/info/funding-tenders/opportunities/portal/screen/home
	Fondazione Telethon https://www.fondazionetelethon.it/chi-siamo/la-fondazione/
	Fondazione italiana autismo https://www.fondazione-autismo.it/

Ongoing collaborations

We are part of TRAIN - TRentino Autism INitiative https://projects.unitn.it/train/ 

Stefano Gustincich, S.I.S.S.A - IIT Genova https://www.iit.it/people/stefano-gustincich 

Stefano Espinoza, Università del Piemonte Orientale (University of Eastern Piedmont) https://upobook.uniupo.it/stefano.espinoza 

Emilio Cusanelli, Laboratory of Cell Biology and Molecular Genetics, CIBIO - Trento https://www.cibio.unitn.it/501/laboratory-of-cell-biology-and-molecular-genetics 

Toma Tebaldi, Laboratory of RNA and Disease Data Science, CIBIO - Trento https://www.cibio.unitn.it/1349/laboratory-of-rna-and-disease-data-science 

Albert Basson, Clinical and Biomedical Sciences, University of Exeter Medical School (UK) http://bassonlab.paulkainth.co.uk/ 

Laura Andreae, King’s College, London (UK). https://www.kcl.ac.uk/people/laura-andreae 

Christelle Golzio, Department of Translational Medicine and Neurogenetics, Institut de Génétic et de Bioligie Moléculare et Cellulare - IGBMC https://www.igbmc.fr/en/recherche/teams/study-of-copy-number-variants-in-autism-spectrum-disorders-and-their-comorbidities 

Ulrika Marklund, Department of Medical Biochemistry and Biophysics, Karolinska Institutet (Sweden). https://ki.se/en/research/research-areas-centres-and-networks/research-groups/neural-cell-diversity-in-the-enteric-nervous-system-ens-ulrika-marklund-group 

Frédéric Saudou, Grenoble Institut Neurosciences, Team “Intracellular Dynamics and Neurodegeneration” https://neurosciences.univ-grenoble-alpes.fr/en/research/research-teams/team-intracellular-dynamics-and-neurodegeneration

Selected publications

Complete List of Published Work could be found here: https://pubmed.ncbi.nlm.nih.gov/?term=Biagioli+Marta&show_snippets=off

Veronica Galli, Sara Vinciguerra, Marta Biagioli, Jasmin Morandell (2025). Circular RNAs as disease modifiers of complex neurologic disorders. Frontiers in Pharmacology. 16:1577496. doi: 10.3389/fphar.2025.1577496.

Francesca Di Leva, Michele Arnoldi, Stefania Santarelli, Mathieu Massonot, Marianne Lemée, Carlotta Bon, [……], Stefano Gustincich, Stefano Espinoza, Marta Biagioli (2025). SINEUP RNA rescues molecular phenotypes associated with CHD8 suppression in autism spectrum disorder model systems. Molecular Therapy. 33(3):1180-1196. doi: 10.1016/j.ymthe.2024.12.043.

Jasmin Morandell, Alan Monziani, Martina Lazioli, Deborah Donzel, Jessica Döring, Claudio Oss Pegorar, Angela D’Anzi, Miguel Pellegrini, Andrea Mattiello, Dalia Bortolotti, Guendalina Bergonzoni, Takshashila Tripathi, Virginia B. Mattis, Marina Kovalenko, Jessica Rosati, Christoph Dieterich, Erik Dassi, Vanessa C. Wheeler, Zdenka Ellederová, Jeremy E. Wilusz, Gabriella Viero, Marta Biagioli (2024). CircHTT(2,3,4,5,6) — co-evolving with the HTTCAG-repeat tract — modulates Huntington's disease phenotypes. Molecular Therapy Nucleic Acids. 35(3):102234. doi: 10.1016/j.omtn.2024.102234.

Dilara Ayyildiz, Guendalina Bergonzoni, Alan Monziani, Takshashila Tripathi, Jessica Döring, Emanuela Kerschbamer, Francesca Di Leva, Elia Pennati, Luisa Donini, Marina Kovalenko, Jacopo Zasso, Luciano Conti, Vanessa C. Wheeler, Christoph Dieterich, Silvano Piazza, Erik Dassi, Marta Biagioli (2023). CAG repeat expansion in the Huntington's disease gene shapes linear and circular RNAs biogenesis. PLoS Genetics. 19(10):e1010988. doi: 10.1371/journal.pgen.1010988.

Emanuela Kerschbamer, Michele Arnoldi, Takshashila Tripathi, Miguel Pellegrini, Samuele Maturi, Serkan Erdin, Elisa Salviato, Francesca Di Leva, Endre Sebestyén, Erik Dassi, Giulia Zarantonello, Matteo Benelli, Eric Campos, M. Albert Basson, James F. Gusella, Stefano Gustincich, Silvano Piazza, Francesca Demichelis, Michael E. Talkowski, Francesco Ferrari, Marta Biagioli (2022). CHD8 Suppression Impacts on Histone H3 Lysine 36 Trimethylation and Alters RNA Alternative Splicing. Nucleic Acids Research. 50(22):12809-12828. doi: 10.1093/nar/gkac1134.

Michele Arnoldi, Giulia Zarantonello, Stefano Espinoza, Stefano Gustincich, Francesca Di Leva, Marta Biagioli (2022). Design and Delivery of SINEUP: A New Modular Tool to Increase Protein Translation. Methods in Molecular Biology. 2434:63-87. doi: 10.1007/978-1-0716-2010-6_4.

Miguel Pellegrini, Guendalina Bergonzoni, Federica Perrone, Ferdinando Squitieri, Marta Biagioli (2022). Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington's Disease. Genes (Basel). 13(11):2017. doi: 10.3390/genes13112017.

Giulia Zarantonello, Michele Arnoldi, Michele Filosi, Toma Tebaldi, Giovanni Spirito, Anna Barbieri, Stefano Gustincich, Remo Sanges, Enrico Domenici, Francesca Di Leva, Marta Biagioli (2021). Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase. Frontiers in Genetics. 12:745229. doi: 10.3389/fgene.2021.745229.

Guendalina Bergonzoni, Jessica Döring, Marta Biagioli (2021). D1R- and D2R-Medium-Sized Spiny Neurons Diversity: Insights Into Striatal Vulnerability to Huntington’s Disease Mutation. Frontiers in Cellular Neuroscience. 15:628010. doi: 10.3389/fncel.2021.628010.

Vidya Murthy, Toma Tebaldi, Toshimi Yoshida, Serkan Erdin, Teresa Calzonetti, Ravi Vijayvargia, Takshashila Tripathi, Emanuela Kerschbamer, Ihn Sik Seong, Alessandro Quattrone, Michael E. Talkowski, James F. Gusella, Katia Georgopoulos, Marcy E. MacDonald, Marta Biagioli (2019). Hypomorphic mutation of the mouse Huntington’s disease gene orthologue. PLoS Genetics. 15(3):e1007765. doi: 10.1371/journal.pgen.1007765.