Biology subjects

Mansouri, S.

Publications and source records attributed to Mansouri, S..

8 recordsLinked to original sources

bioRxiv2026

Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma

Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.

cancer biology↗

bioRxiv2025

SAME: Topology-flexible transforms enable robust integration of multimodal spatial omics

Spatial omics technologies provide complementary and layered molecular insights that span proteins, transcripts, and metabolites. However, aligning and integrating these modalities across serial tissue sections remains a computational challenge. Existing alignment methods are primarily unimodal and assume preserved topology, often failing with tissue distortions like tears, folds, or anatomical changes. Here, we present SAME (Spatial Alignment of Multimodal Expression) that introduces space-tearing transforms, a framework for controlling localized topological disruptions during cross-sectional alignment. Using integer linear programming to maximize cell type matches across the modalities, we enhance cell-type alignment accuracy by 20% compared to existing methods while preserving biologically meaningful spatial relationships. Applied to protein-RNA integration in healthy tongue tissue and lung adenocarcinoma, SAME revealed cryptic immune subpopulations that were otherwise missed by RNA-only or protein-only classification. In a separate lung adenocarcinoma study, we assayed and integrated protein and metabolomic profiles, uncovering localized mevalonic acid upregulation specifically within tumor-macrophage spatial niches and identifying targeted metabolic crosstalk invisible to single-modality approaches. SAME enables unprecedented experimental designs that leverage each modality independently while computationally recovering cross-modal spatial structure, unlocking multimodal discoveries in complex tissues.

bioinformatics↗

bioRxiv2025

Disrupted α-ketoglutarate homeostasis trains monocyte-derived macrophages towards M2-like phenotype in long-term treated HIV-infection

Cells of the myeloid lineage, particularly monocytes and macrophages, are central to HIV pathogenesis, contributing to viral persistence and immune regulation during suppressive therapy. We hypothesized that metabolic reprogramming and altered chemokine signaling in people with HIV (PWH) on long-term ART impair monocyte trafficking and macrophage polarization. Using single-cell RNA sequencing, immunophenotyping, and metabolic modeling, we identified altered receptor expression and disrupted metabolic flux linked to reduced monocyte migration. Plasma secretome profiling revealed a nonclassical inflammatory microenvironment, while integrative multi-omics and single-cell proteomics of monocyte-derived macrophages (MDMs) demonstrated metabolic rewiring of the Glycolysis-TCA Anaplerosis Axis, orchestrated in part by elevated -ketoglutarate (AKG). Differentiation with PWH serum or AKG, skewed MDMs toward an M2-like phenotype, and enhanced HIV susceptibility. Together, these systems-level and mechanistic analyses reveal that metabolic training drives macrophage dysfunction in well-treated PWH, sustaining low-grade inflammation and highlighting potential therapeutic targets.

systems biology↗

bioRxiv2024

Transcriptional profiling of the cortico-accumbal pathway reveals sex-specific alterations underlying stress susceptibility

Anxiety and depressive disorders, including major depressive disorder (MDD), affect millions of people every year, imposing significant socio-economic burdens. In this scenario, current treatments for MDD show limited efficacy, highlighting the need to better understand its molecular mechanisms. The medial prefrontal cortex (mPFC) has been identified as a critical brain region in MDD pathology, displaying altered activity and morphology. This study targets the mPFC-to-nucleus accumbens (NAc) pathway, which is implicated in the regulation of emotional behavior. We used a pathway-specific approach to uncover transcriptional profiles in mPFC neurons projecting to the NAc in stressed male and female mice. Using the RiboTag technique and RNA sequencing, we identified sex-specific gene expression changes, revealing potential roles in stress susceptibility. Differential expression and weighted gene co-expression network analyses revealed distinct transcriptional responses to chronic stress in males and females. Key findings include the identification of the X-linked lymphocyte-regulated 4B (Xlr4b) gene, within a highly relevant gene module, as a stress susceptibility driver in males. By experimentally overexpressing the Xlr4b gene, we characterized its crucial role in regulating neuronal firing and influencing arborization patterns to promote anxiety-like behavior in a sex-specific fashion. These findings suggest that chronic stress induces unique and shared transcriptional alterations in mPFC neurons projecting to the NAc. Some of these alterations change the morphological and functional properties of neuronal pathways ultimately contributing to the differential manifestation of anxiety-like and depressive-like behaviors in male and female mice.

neuroscience↗

bioRxiv2024

Metabolic alterations drive inflammatory phenotypes in CHIP-associated heart failure

Mutations in DNA methyltransferase 3 alpha (DNMT3A) are the most frequent driver of clonal hematopoiesis of indeterminate potential (CHIP), and associated with higher risk of cardiovascular disease and pro-inflammatory activation of immune cells. Here, we investigated the mechanisms underlying DNMT3A CHIP-associated inflammatory phenotypes in macrophages. We show that monocytes of DNMT3A CHIP-driver mutation carriers are associated with DNA hypomethylation of succinate dehydrogenase A (SDHA) and an altered tricarboxylic acid cycle metabolite profile. Silencing of DNMT3A in monocytes increased SDHA and elevated mitochondria complex II activity. The secreted complex II product, malate, further increased inflammatory activation in wild type monocytes to further augment inflammation in a paracrine manner. Pharmacological inhibition of SDHA (using dimethyl malonate) in mice harboring DNMT3A mutations in hematopoietic stem cells ameliorated the inflammatory response and improved cardiac function after myocardial infarction. Thus, interfering with the altered metabolic state may provide a new therapeutic option to dampen inflammatory activation in DNMT3A CHIP carrying patients.

molecular biology↗

bioRxiv2023

Neutrophil efferocytosis reprograms mitochondrial metabolism to switch alveolar macrophages to a pro-resolution phenotype at the cost of bacterial control

Resolution of lung injuries is vital to maintain gas exchange. Concurrently, there is an increased risk of secondary bacterial infections. Alveolar macrophages (AMs) are crucial to clear bacteria and control initiation and resolution of inflammation, but environmental cues that switch functional phenotypes of AMs remain elusive. Here, we discovered an incapacity of AMs to mount an effective immune response to bacteria during resolution of inflammation. AM efferocytosis of neutrophils (PMNs), a hallmark of resolution of inflammation, switched mitochondrial metabolism to shift AM functions. Mechanistically, PMN-derived myeloperoxidase (MPO) fueled canonical glutaminolysis via uncoupling protein 2 (UCP2) resulting in decreased mtROS-dependent killing of bacteria and secretion of pro-inflammatory cytokines. Instead, MPO-enhanced UCP2 expression inhibited mitochondrial hyperpolarization and boosted efferocytosis irrespective of the presence of bacterial pathogens. In contrast, efferocytosis of epithelial cells resulted in a distinct anti-inflammatory phenotype of AMs maintaining phenotypic plasticity towards bacteria. Overall, uptake of apoptotic PMNs switches AMs to prioritize resolution of inflammation over antibacterial responses and similarly affects murine macrophages at extra-pulmonary sites, and human AMs. One sentence summaryNeutrophil efferocytosis reprograms mitochondrial metabolism to switch alveolar macrophages to a pro-resolution phenotype at the cost of bacterial control.

immunology↗

bioRxiv2020

Sex-specific retinal anomalies induced by chronic social stress in mice

Major depressive disorder (MDD) is one of the most common consequences of chronic stress. Still, there is currently no reliable biomarker to detect individuals at risk to develop MDD. Recently, the retina emerged as an effective way to approach the brain and investigate psychiatric disorders with the use of the electroretinogram (ERG). In this study, cones and rods ERGs were performed in male and female mice before and after chronic social defeat stress (CSDS). Mice were then divided as susceptible or resilient to stress. Significant results were only observed in rods ERGs. In males, susceptible mice showed prolonged a-wave implicit times at baseline that were shortened after CSDS. The a-wave was also decreased in both susceptible and resilient male mice after CSDS. In females, rod a-waves were shorter in susceptible than in control mice after CSDS resulting from the latter demonstrating delayed a-waves. Baseline ERGs were able to predict - to some extent - the expression of susceptibility and resilience before stress exposition in male and female mice. Overall, our findings suggest that retinal activity is a presumptive biomarker of stress response and that the ERG could potentially serve as a predicting tool of the stress response in mice.

neuroscience↗

bioRxiv2020

Mucosal vaccine adjuvant cyclic di-GMP differentiates lung moDCs into Bcl6+ and Bcl6- mature moDCs to induce lung memory CD4+ TH cells and lung TFH cells respectively

Induction of lung T-cell responses, including memory CD4+ TH and TFH cells, are highly desirable for vaccines against respiratory infections. We recently showed that the non-migratory monocytes-derived DCs (moDCs) induced lung TFH cells. However, the DCs subset inducing lung CD4+ memory TH cells is unknown. Here, using conditional knockout mice and adoptive cell transfer, we first established that moDCs are essential for lung mucosal, but are dispensable for systemic, vaccine responses. Next, we showed that intranasal administration of adjuvant cyclic di-GMP differentiated lung moDCs into Bcl6+ and Bcl6- moDCs promoting lung memory TH cells and lung TFH cells, respectively. Mechanistically, soluble TNF from lung TNFR2+ cDC2 subpopulation mediates the induction of lung Bcl6+ moDCs. Last, we designed fusion proteins targeting soluble or transmembrane TNF to lung moDCs and generated Bcl6+, Bcl6- lung moDCs respectively. Together, our study revealed lung mature moDCs heterogeneity and showed a moDCs-targeting strategy to enhance lung mucosal vaccine responses.

immunology↗