Biology subjects

Marquez, A.

Publications and source records attributed to Marquez, A..

4 recordsLinked to original sources

bioRxiv2025

Genome-wide DNA methylation study reveals specific signatures in the affected arterial tissue of giant cell arteritis patients

ObjectivesGiant cell arteritis (GCA) is a large-vessel vasculitis, potentially causing complications such as blindness and strokes. This study aims to gain insights into the pathogenesis of GCA by identifying specific DNA methylation signatures in the arterial tissue of patients with this vasculitis. MethodsDNA methylation profiling was analyzed in 79 temporal artery biopsy samples (69 patients with GCA and 10 controls) by performing an epigenome-wide association study (EWAS). Differential analysis was performed to identify differentially methylated positions (DMPs) and regions (DMRs). Lastly, we compared our findings with previous transcriptomics and epigenomics studies on GCA-affected arteries. ResultsEWAS identified 3,644 DMPs (FDR < 0.05, |{Delta}{beta}| > 0.3), indicating a profound alteration within GCA-affected arterial tissue. These DMPs were annotated to 1,517 potentially dysregulated genes. 282 additional genes were identified by annotation of significant DMRs. Pathway enrichment analysis revealed a significant alteration of inflammatory mechanisms, such as interleukins 2 and 7, as well as pathways related to vascular remodeling. Omics study comparison revealed 37 genes consistently affected across datasets, many of them linked to immune signaling and T cell regulation. Notably, markers of exhausted T cells, including SLAMF6 and HAVCR2, were present among them. ConclusionsOur study identified GCA-specific DNA methylation signatures in arterial tissue, revealing disrupted inflammatory and vascular pathways, and suggesting the involvement of exhausted T cells in this condition. These findings offer new insights into GCA pathogenesis and provide new potential targets for the treatment of this debilitating disease. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABS{square} Affected arteries by giant cell arteritis (GCA) exhibit unique epigenetic signatures, reflecting significant disruptions in gene regulation. However, small sample sizes have constrained the clinical translation and broader interpretation of these findings, leaving key gaps in understanding GCA pathogenesis and identifying therapeutic targets. What this study adds{square} This study provides the largest-to-date epigenome-wide DNA methylation profiling in GCA-affected arteries, uncovering thousands of epigenetic changes and revealing profound disruptions in inflammatory and vascular pathways, including IL-2, IL-7, and CXCR4 signaling. {square}We compiled 37 genes consistently affected across different omics datasets in GCA-affected arteries, providing a robust list of candidates for further research into GCA pathogenesis and treatment. {square}Our findings provide evidence of T cell exhaustion in GCA-affected arteries, supported by consistent changes in key markers such as SLAMF6 and HAVCR2 (TIM-3), suggesting a novel mechanism of immune dysregulation in GCA. How this study might affect research, practice or policy{square} This study nominates exhausted T cells, the NLRP3 inflammasome, and CXCR4 signaling as novel contributors in GCA pathogenesis, suggesting new therapeutic targets for further research in the treatment of this disease.

immunology↗

bioRxiv2023

Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction

ApoE4 is the primary risk factor for Alzheimer Disease (AD). Early AD pathological events first affect the neuronal endolysosomal system, which in turn causes neuronal protein aggregation and cell death. Despite the crucial influence of lysosomes upon AD pathophysiology, and that apoE4 localizes to lysosomes, the influence of apoE4 on lysosomal function remains unexplored. We find that expression of apoE4 in neuronal cell lines results in lysosomal alkalinization and impaired lysosomal function. To identify driving factors for these defects, we performed quantitative lysosomal proteome profiling. This revealed that apoE4 expression results in differential regulation of numerous lysosomal proteins, correlating with apoE allele status and disease severity in AD brains. In particular, apoE4 expression results in the depletion of lysosomal Lgals3bp and the accumulation of lysosomal Tmed5. We additionally validated that these lysosomal protein changes can be targeted to modulate lysosomal function. Taken together, this work thereby reveals that apoE4 causes widespread lysosomal defects through remodeling the lysosomal proteome, with the lysosomal Tmed5 accumulation and Lgals3bp depletion manifesting as lysosomal alkalinization in apoE4 neurons.

neuroscience↗

bioRxiv2020

A quantitative principle to understand 3D cellular connectivity in epithelial tubes

Epithelial cell organization and the mechanical stability of tissues are closely related. In this context, it has been recently shown that packing optimization in bended/folded epithelia is achieved by a surface tension energy minimization mechanism that leads to a novel cellular shape: the scutoid. However, further cellular and tissue level implications of this new developmental paradigm remain unknown. Here we focus on the relationship between this complex cellular shape and the connectivity between cells. We address this problem using a combination of computational, experimental, and biophysical approaches in tubular epithelia. In particular, we examine how energy drivers affect the three-dimensional packing of these tissues. We challenge our biophysical model by reducing the cell adhesion in epithelial cells. As a result, we observed an increment on the cell apico-basal intercalation propensity that correlated with a decrease of the energy barrier necessary to connect with new cells. We conclude that tubular epithelia satisfy a quantitative biophysical principle, that links tissue geometry and energetics with the average cellular connectivity.

developmental biology↗

bioRxiv2017

Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF and NF1 loss

Oncogenic alterations in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS, BRAF, and loss of the tumor suppressor and RAS GTPase-activating protein (GAP) NF1, drive the growth of a wide spectrum of human cancers. While BRAF and MEK inhibitors are effective in many patients with oncogenic BRAF V600E, there are no effective targeted therapies for individuals with cancers driven by other pathway alterations, including oncogenic KRAS, non-V600E BRAF, and NF1 loss. Here, we show that targeting the PTPN11/SHP2 phosphatase with a novel small molecule allosteric inhibitor is effective against cancers bearing nucleotide-cycling oncogenic RAS (e.g. KRAS G12C), RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants), or NF1 loss in multiple preclinical models in vitro and in vivo. SHP2 inhibition suppressed the levels of RAS-GTP and phosphorylated ERK in these models and induced growth inhibition. Expression of a constitutively active mutant of the RAS guanine nucleotide exchange factor (GEF) SOS1 rescued cells from the effects of SHP2 inhibition, suggesting that SHP2 blockade decreases oncogenic RAS-RAF-MEK-ERK signaling by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS activation and downstream signaling in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF, and NF1 loss. SHP2 inhibition thus represents a rational, biomarker-driven therapeutic strategy to be tested in patients with cancers of diverse origins bearing these oncogenic drivers and for which current treatments are largely ineffective.

cancer biology↗