Biology subjects

Antonini, D.

Publications and source records attributed to Antonini, D..

5 recordsLinked to original sources

bioRxiv2026

p63 and p73 regulate convergent and factor-specific transcriptional programs in cutaneous squamous cell carcinoma

Aberrant transcriptional regulation is a defining feature of squamous cell carcinoma (SCC), yet how lineage transcription factors coordinate shared and factor-specific oncogenic programs remains poorly understood. Although TP63 (p63) is frequently amplified in SCC, the contribution of its paralog TP73 (p73) has remained unclear. Here we show that p73, together with p63, is upregulated in skin SCC and is required for tumorigenesis. Mechanistically, p63 and p73 form heteromeric complexes and co-occupy distal enhancer elements, establishing a shared chromatin regulatory framework. Integration of chromatin and transcriptomic profiling reveals that this common enhancer landscape supports both convergent and divergent transcriptional outputs. Both factors cooperatively sustain core proliferation but also exert regulatory biases, with p63 preferentially reinforcing epithelial lineage circuits and p73 contributing to DNA replication and stress-associated pathways. Among shared downstream targets, p63/p73 co-regulation of multiple epidermal growth factor receptor (EGFR) ligands establishes a feed-forward signaling module that amplifies mitogenic signaling. Amphiregulin emerges as a dominant functional mediator, and its depletion phenocopies key aspects of p63/p73 loss, including impaired proliferation and tumor formation. Together, these findings support a model in which shared enhancer occupancy by p63 and p73 drives cooperative and factor-specific transcriptional programs, linking chromatin regulation to signaling and tumor maintenance.

molecular biology↗

bioRxiv2025

Targeted p63 isoform switch corrects dominant mutations in AEC syndrome without disrupting epidermal homeostasis

The transcription factor p63 is a master regulator of stratified epithelial development, and its disruption causes severe congenital defects affecting the skin, limbs, and craniofacial structures in both humans and mice. Among p63-related disorders, Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome is caused by dominant mutations primarily affecting the Sterile Alpha Motif (SAM) domain and the Transactivation Inhibitory Domain (TID) of the TP63 gene, which are unique to the p63 isoform. These mutations promote protein aggregation and transcriptional dysregulation, ultimately leading to debilitating skin erosions, suggesting that isoform-specific strategies could be therapeutically relevant. To explore a therapeutic strategy based on isoform switching, we generated a conditional mouse model with deletion of exon 13, resulting in replacement of p63 by the shorter p63{beta} isoform, which is expressed in the skin at lower levels. Although we found that p63 is required for limb and palate development, p63{beta} proved sufficient to support epidermal formation, postnatal skin homeostasis, and wound healing. At the molecular level, the switch from p63 to p63{beta} preserved chromatin binding and global transcriptional programs in keratinocytes. We next used genome editing to delete exon 13 in human primary keratinocytes, inducing a switch from p63 to p63{beta}. This isoform switch maintained normal proliferation and global gene expression. Importantly, p63{beta} expression in AEC patient-derived keratinocytes rescued protein aggregation, restored mechanical integrity, and normalized epidermal gene expression. Together, these findings demonstrate that p63{beta} can functionally compensate for p63 in the skin and establish and indicate that isoform switching could offer a new treatment option for AEC syndrome.

molecular biology↗

bioRxiv2024

Ezrin defines TSC1 activation at endosomal compartments through EGFR-AKT signaling

Endosomes have emerged as major signaling hubs where different internalized ligand-receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane-actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.

cell biology↗

bioRxiv2024

Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy

LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy. This often-lethal disease is triggered by mutations in LAMA2, coding for laminin-2 chain, a key extracellular matrix (ECM) component, prevalent in the skeletal muscle. Several phenotypes have been associated with LAMA2-CMD, however, it is not yet known what mechanisms are faulty, right at disease onset in utero. Using the dyW mouse model of LAMA2-CMD we showed that the disease onset is characterized by a profound downregulation of gene expression, with a marked effect on cytoskeletal organization, myoblast differentiation and fusion and altered DNA repair and oxidative stress responses. Concordantly, we found that Lama2-deficient myoblast cells displayed proliferation and differentiation defects, increased oxidative stress and DNA damage. Together, our findings provide unique insights into the processes dependent on laminin-2 chain during muscle development, revealing its critical importance to maintain muscle cell homeostasis already at fetal stages.

developmental biology↗

bioRxiv2018

Positive selection in Europeans and East-Asians at the ABCA12 gene

Natural selection acts on genetic variants by increasing the frequency of alleles responsible for a cellular function that is favorable in a certain environment. In a previous genome-wide scan for positive selection in contemporary humans, we identified a signal of positive selection in European and Asians at the genetic variant rs10180970. The variant is located in the second intron of the ABCA12 gene, which is implicated in the lipid barrier formation and down-regulated by UVB radiation. We studied the signal of selection in the genomic region surrounding rs10180970 in a larger dataset that includes DNA sequences from ancient samples. We also investigated the functional consequences of gene expression of the alleles of rs10180970 and another genetic variant in its proximity in healthy volunteers exposed to similar UV radiation.\n\nWe confirmed the selection signal and refine its location that extends over 35 kb and includes the first intron, the first two exons and the transcription starting site of ABCA12. We found no obvious effect of rs10180970 alleles on ABCA12 gene expression. We reconstructed the trajectory of the T allele over the last 80,000 years to discover that it was specific to H. sapiens and frequent among non-Africans already 45,000 years ago.

genomics↗