Biology subjects

Chiacchiera, F.

Publications and source records attributed to Chiacchiera, F..

4 recordsLinked to original sources

bioRxiv2026

A generative network model reveals hierarchical structural memory guiding post-mitotic 3D genome inheritance

How three-dimensional (3D) genome organization is reestablished after mitosis to preserve gene regulatory programs and cell identity remains unresolved. We asked whether mitotic chromosome architecture contributes to cellular memory by preserving structural information while maintaining the flexibility required for cellular adaptation. Here we introduce HiCONA, a generative Bayesian framework that infers hierarchical genome organization and quantifies the structural contribution of individual interactions through an Entropy Impact Score. HiCONA resolves genome organization across multiple scales, revealing structure-defining interaction patterns underlying chromatin architecture, independently of experimental modality. We identify structurally impactful chromatin interactions retained during mitosis delineating distinct trajectories of post-mitotic genome reassembly. These mitotically preserved interactions are enriched for active, transcriptionally competent regulatory elements, consistent with a cis-encoded architectural memory subsequently remodeled by trans-acting regulators. Together, our findings suggest that molecular information retained on mitotic chromosomes guides structural trajectories, providing an architectural basis for epigenetic memory and post-mitotic genome inheritance.

genomics↗

bioRxiv2025

Non-neuronal, TGF-β- extracellular matrix restructuring promotes neurodegeneration in a PSP-Richardson syndrome model

Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a rapidly progressive tauopathy lacking effective therapies. Although tau aggregation is a defining feature, the initiating mechanisms remain elusive. Here we used patient-derived induced pluripotent stem cell midbrain organoids, integrating single-cell transcriptomics, bulk RNA profiling, and quantitative proteomics, to dissect early pathogenic events. We identified vascular leptomeningeal-like cells (VLMCs) as the first altered population, exhibiting TGF-{beta}-driven extracellular matrix (ECM) remodeling enriched in collagens, integrins, and TGFBI. The resulting pathological ECM increased stiffness, induced integrin clustering, and activated RhoA-ROCK-mediated cytoskeletal disorganization. These changes sustained PI3K-AKT and MAPK-ERK signaling, suppressed PP2A, hyperactivated mTOR, and impaired autophagy, culminating in tau hyperphosphorylation and mislocalization. Pharmacological inhibition of TGF-{beta}, AKT, ERK, or mTORC1 restored autophagic flux, reduced tau burden, and rescued neuronal architecture. Our findings establish non-neuronal, matrix-producing niche cells as upstream drivers of tauopathy and reveal TGF-{beta}-mediated ECM restructuring as a mechanochemical trigger of neurodegeneration, opening multiple therapeutic avenues for PSP-RS and related tauopathies.

neuroscience↗

bioRxiv2024

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

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in directing body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling promotes cell lineage identity in different tissues is often missing. Here, leveraging prostate organoid technology, we demonstrated that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and ultimately, proper specification of the prostatic lumen. Mechanistically, RA-dependent RAR{gamma} activation promotes the expression of the pioneer factor Foxa1, which synergizes with the androgen pathway for proper luminal expansion, cytoarchitecture and function. FOXA1 nucleotide variants are common in human prostate and breast cancers and considered driver mutations, though their pathogenic mechanism is incompletely understood. Combining functional genetics experiments with structural modeling of FOXA1 folding and chromatin binding analyses, we discovered that FOXA1F254E255 is a loss-of-function mutation leading to compromised transcriptional function and lack of luminal fate commitment of prostate progenitors. Overall, we define RA as a crucial instructive signal for glandular identity in adult prostate progenitors. We propose deregulation of vitamin A metabolism as a risk factor for benign and malignant prostate disease, and identified cancer associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors. Summary: Retinoic acid signaling orchestrates luminal differentiation of adult prostate progenitors

cancer biology↗

bioRxiv2019

Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz

Background & AimsActivation of MYC and CTNNB1 (encoding {beta}-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.\n\nApproach & ResultsWe generated a mouse model allowing conditional activation of MYC and WNT/{beta}-catenin signaling (through either {beta}-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Conditional activation of WNT/{beta}-catenin signaling strongly accelerated MYC-driven carcinogenesis in the mouse liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and {beta}-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a \"Myc/{beta}-catenin signature\", composed of a discrete set of Myc-activated genes whose expression increased in presence of active {beta}-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/{beta}-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/{beta}-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/{beta}-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.\n\nConclusionsYap and Taz mediate the cooperative action of Myc and {beta}-catenin in liver tumorigenesis. This warrants efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/{beta}-catenin activity.

cancer biology↗