publications

2025

1. brain

   MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis

   Paolo Vincenzo Fioretti, Anna Barbieri, Alice Migazzi, and 48 more authors

   Brain, Sep 2025

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   Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice, and patient-derived cells modeling TDP-43, SOD1, and C9orf72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioral abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived EVs that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.

2. iScience

   Distinct microRNA signatures define sporadic PSP-RS and PD in patient-derived midbrain organoids

   Desirèe Valente, Clara Zannino, Stefania Scalise, and 12 more authors

   iScience, Aug 2025

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   Progressive supranuclear Palsy-Richardson syndrome (PSP-RS) is a rare, rapidly progressive tauopathy often misdiagnosed as Parkinson’s disease (PD) due to overlapping clinical features and the lack of reliable molecular biomarkers. To address this need, we generated human midbrain organoids from induced pluripotent stem cells (iPSCs) derived from individuals with sporadic PSP-RS, PD, and healthy controls (HCs), and performed longitudinal small RNA sequencing to profile microRNA (miRNA) signatures. These 3D organoids recapitulated disease-relevant pathologies, including tau hyperphosphorylation in PSP-RS and α-synuclein aggregation in PD. Transcriptomic analysis revealed dynamic, disease-specific miRNA signatures. Notably, miR-5683, miR-873-5p, miR-219b-5p, and miR-219a-2-3p were enriched in PSP-RS, while PD organoids showed increased expression of miR-1-3p and miR-133b. Differential expression analysis identified miR-5683, miR-3085-3p, and miR-124-3p as robust classifiers distinguishing PSP-RS from controls. Our findings support iPSC-derived midbrain organoids as a relevant platform for modeling atypical parkinsonian syndromes and uncovering candidate miRNA biomarkers for early and differential diagnosis.

3. Ann. Neurol.

   Modeling sporadic progressive supranuclear palsy in 3D midbrain organoids: Recapitulating disease features for in vitro diagnosis and drug discovery

   Elvira Immacolata Parrotta, Valeria Lucchino, Clara Zannino, and 13 more authors

   Ann. Neurol., Jan 2025

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   ObjectiveProgressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP‐Richardson’s syndrome (PSP‐RS) using multi‐donor midbrain organoids (MOs).MethodsThe MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP‐RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R‐tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology.ResultsPSP‐derived MOs showed progressive size reduction compared with HC‐derived MOs, linked to upregulated apoptosis‐related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP‐positive cells in PSP‐derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted‐shaped astrocytes, absent in HC‐derived organoids.InterpretationWe developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025

2024

1. Nargab

   SpikeFlow: automated and flexible analysis of ChIP-Seq data with spike-in control

   Davide Bressan, Daniel Fernández-Pérez, Alessandro Romanel, and 1 more author

   NAR Genomics and Bioinformatics, Aug 2024

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   ChIP with reference exogenous genome (ChIP-Rx) is widely used to study histone modification changes across different biological conditions. A key step in the bioinformatics analysis of this data is calculating the normalization factors, which vary from the standard ChIP-seq pipelines. Choosing and applying the appropriate normalization method is crucial for interpreting the biological results. However, a comprehensive pipeline for complete ChIP-Rx data analysis is lacking. To address these challenges, we introduce SpikeFlow, an integrated Snakemake workflow that combines features from various existing tools to streamline ChIP-Rx data processing and enhance usability. SpikeFlow automates spike-in data scaling and provides multiple normalization options. It also performs peak calling and differential analysis with distinct modalities, enabling the detection of enrichment regions for histone modifications and transcription factor binding. Our workflow runs in-depth quality control at all the processing steps and generates an analysis report with tables and graphs to facilitate results interpretation. We validated the pipeline by performing a comparative analysis with DiffBind and SpikChIP, demonstrating robust performances in various biological models. By combining diverse functionalities into a single platform, SpikeFlow aims to simplify ChIP-Rx data analysis for the research community.

2. EmboPress

   Rarγ-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

   Dario De Felice, Alessandro Alaimo, Davide Bressan, and 18 more authors

   EMBO reports, Aug 2024

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   Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RARγ activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1F254E255 is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

3. Sci. Adv.

   Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations

   A. D’Ambrosio, D. Bressan, and E. Ferracci

   Science Advances, Mar 2024

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   Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.

   @article{paperArid1a,
     title = {Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations},
     author = {D'Ambrosio, A. and Bressan, D. and Ferracci, E.},
     journal = {Science Advances},
     volume = {10},
     issue = {11},
     pages = {eadh4435},
     numpages = {0},
     year = {2024},
     month = mar,
     publisher = {American Association for the Advancement of Science,},
     doi = {10.1126/sciadv.adh4435},
     url = {https://www.science.org/doi/10.1126/sciadv.adh4435},
     dimensions = {true},
   }

2023

1. Oral Talk

   Increased genomic instability and reshaping of tissue microenvironment drive ARID1A-dependent cancer formation

   D. Bressan

   SIBBM 2023. Frontiers in Molecular Biology - Bari, IT, Jun 2023

2022

1. Poster

   The role of mSWI/SNF complex in preserving liver tissue homeostasis and preventing hepatocellular carcinoma formation

   D. Bressan, A D’Ambrosio, and E. Ferracci

   PEZCOLLER SYMPOSIUM - Trento, IT, Jun 2022
2. Poster

   Role of the mSWI/SNF chromatin remodeling complex in preserving liver homeostasis

   D. Bressan, A D’Ambrosio, and E. Ferracci

   EACR - Seville, SP, Jun 2022