👤 Simon-Pierre Gravel

Abdominal aortic aneurysm (AAA) is a serious disease with no effective pharmacological therapy. Although inflammation is recognized as a key regulator of AAA, targeting inflammatory pathways once the disease is established does not improve outcomes. Understanding the earliest molecular indicators could clarify precise biological targets and prognostic markers for AAA. Using ApoE-deficient mice, we performed RNA-Seq on suprarenal abdominal aortas (SRAs) from Ang II- and saline-treated mice 24 h after infusion. We further developed a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) can be conditionally suppressed in vascular smooth muscle cells (VSMCs). RNA-Seq data revealed early IKKβ-dependent cellular anabolic processes in SRAs, including activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, deletion of the Show less

G protein-coupled receptors (GPCRs) rapidly transmit extracellular signals by activating effector proteins, thereby producing well-characterized second messenger molecules. Free, unanchored polyubiquitin chains have been proposed as secondary messengers in immune and inflammatory pathways that regulate cellular responses to invading pathogens and the inflammatory cytokine Interleukin-1 beta (IL-1β). It remains unknown whether these molecules play a role in GPCR signaling. The present study used primary, immortalized, and transformed cellular models, together with loss-of-function approaches, to demonstrate the presence and functions of unanchored polyubiquitin chains in inflammatory signaling pathways that activate the activator protein 1 (AP-1) and nuclear factor-kappa B (NF-κB) transcription factors. In response to inflammatory GPCR agonists Angiotensin II (Ang II), lysophosphatidic acid (LPA), and thrombin (Thr), the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) controls early signaling events that lead to T-loop phosphorylation of Transforming Growth Factor β-activated kinase 1 (TAK1), IκB kinase beta (IKKβ), c-Jun N-terminal kinases (JNK1/2), and p38 mitogen-activated protein kinases (p38). In parallel, we document the rapid, transient TRAF6-dependent production of unanchored lysine (K)63-linked polyubiquitin chains that accumulate in TAK1 and IKKβ immunocomplexes. Pull-down assays specifically designed to capture unanchored polyubiquitin chains in cellular extracts from stimulated cells further support their transient nature. Lastly, stable expression of a zinc finger ubiquitin-binding protein (ZnF-UBP) domain, which specifically binds unanchored polyubiquitin chains in immortalized keratinocytes exposed to LPA and Thr, shows that this production occurs in the proximity to the plasma membrane and diminishes the T-loop phosphorylation of TAK1, IKKβ, JNK1/2, and p38, thereby affecting the induction of early transcriptional events. Our results support a novel paradigm in GPCR signal transduction, identifying unanchored K63-linked polyubiquitin chains as second messenger molecules. The online version contains supplementary material available at 10.1186/s12964-025-02646-6. Show less

The 17q21.31 locus in humans harbors several complex structural haplotypes including a ~970kb inversion. Different inversion haplotypes have been associated with susceptibility to microdeletions causing Koolen-de Vries syndrome and variation in fecundity and recombination rates. Here, using 210 haplotype-resolved human genome assemblies and pangenome graph-based approaches we characterize 11 distinct structural haplotypes, several of which have not been previously described. Extending our analyses to a set of haplotype-resolved great-ape genomes, we characterize the structure of an independent inversion in chimpanzees which extends an additional 650kb, encompasses 5 additional genes, and is ~2 million years younger than the human inversion. We further determine that gorillas exhibit an independent duplication of the Show less

This study explores the cell fate reprogrammability of H3K27M-mutant pediatric high-grade gliomas (pHGG) using neuronal transdifferentiation as a potential targeted therapy. We treated the BT245 patient-derived glioma cell line with pharmacological combinations targeting neuronal differentiation pathways and performed bulk RNA sequencing to characterize gene expression patterns driving cell fate transitions. Our findings reveal that the drug combinations induce transcriptomic changes consistent with differentiation towards neuronal phenotypes, including the upregulation of synaptic and dendritic signaling genes and the downregulation of malignant signatures. In comparison, astrocytic differentiation media (DM) and H3K27M knockout (KO) promote residual astrocytic phenotypes, suggesting neuronal transdifferentiation as a more effective strategy for mitigating tumor aggressiveness and progression. Differentially expressed genes such as GRIK1, GRIN1, NRXN3, NRXN1, CALB2, SCGN, SLC32A1, SLC1A2, KCNC3, and neurodevelopmental regulators including WNT7A, DLX6, ERBB4, ARX, BCL11B, SEMA3C, and FGFBP3 were identified as key markers regulating the neuron-like lineage transition. This study demonstrates that pHGGs can be phenotypically redirected toward neuronal-like identities through modulating cell fate differentiation programs. These findings advance the concept of 'differentiation therapy' as a promising intervention to reduce phenotypic plasticity and malignancy in pHGG ecosystems. While these are early in vitro findings, the potential ability to steer and control glioma cells toward stable, less malignant fates offers promising translational potential for patient-centered targeted therapies. Show less