Biology subjects

Remeseiro, S.

Publications and source records attributed to Remeseiro, S..

6 recordsLinked to original sources

bioRxiv2024

AMPK-activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching

AbstractMetabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease worldwide for which there are no approved treatments. Adenosine monophosphate-activated protein kinase (AMPK) is an interesting therapeutical target since it acts as a central regulator of cellular metabolism. Despite efforts to target the AMPK, no direct activators has yet been approved for treatment of this disease. This study investigates the effect of AMPK activator ATX-304 in a preclinical mouse model of progressive fatty liver disease. The data demonstrate that ATX-304 diminishes body fat mass, lowers blood cholesterol levels, mitigates liver steatosis, and ameliorates the development of liver fibrosis. The beneficial effects of ATX-304 treatment are accompanied by a shift in the liver metabolic program, including increased lipid oxidation, reduced lipid synthesis, as well as remodeling of cholesterol and lipid transport. We also observed variations in lipid distribution among liver lobes in response to ATX-304, and a shift in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggest that ATX-304 holds promise as a potential treatment for Metabolically Associated Fatty Liver Disease (MAFLD), including in human patients.

molecular biology↗

bioRxiv2024

Wnt signaling alters CTCF binding patterns and global chromatin structure

Wnt signaling plays a pivotal role during development, stem cell maintenance, and tissue homeostasis. Upon Wnt pathway activation, {beta}-catenin translocates to the nucleus where it binds the TCF/LEF transcription factors to drive the context-specific expression of Wnt target genes. Coordinating gene expression programs in vertebrates requires a complex interplay between the regulatory and the 3D organization of the genome. However, the impact of Wnt signaling on genome structure has been poorly explored. Here we investigated how Wnt signaling activation influences the binding patterns of CTCF, one of the core architectural proteins that helps establish the 3D genome organization be demarcating topologically associated domains (TAD). This study uncovered a series of CTCF rearrangements under Wnt, that we termed RUW. Notably, RUW sites that were gained upon Wnt activation were typically dependent on {beta}-catenin and were characterized by both CTCF and TCF/LEF binding. Accordingly, many CTCF RUWs aligned with {beta}-catenin binding patterns, and {beta}-catenin and CTCF co-localized in vivo in discreet nuclear puncta only upon pathway activation. Genome-wide investigation of CTCF-mediated 3D genomic interactions upon Wnt pathway stimulation supported the role of the identified RUWs in mediating Wnt-dependent chromatin loops. Lastly, targeted disruption of selected CTCF binding sites demonstrated their functional contribution to Wnt target gene regulation, implicating regulation of the 3D genomic structure in the execution of transcriptional programs orchestrated by developmental pathways.

developmental biology↗

bioRxiv2023

fhl2b expression ameliorates muscular dystrophy

In muscular dystrophies, muscle fibers loose integrity and die, leading to significant suffering and a shorter life. Strikingly, the extraocular muscles (EOMs), controlling eye movements, are spared and function well despite the disease progression. Although EOMs have been shown to have important differences compared to body musculature the mechanisms underlying this inherent resistance to muscle dystrophies remain largely unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscle in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is upregulated in response to knockout of desmin, plectin and obscurin, intermediate filament proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival rate. Therefore, fhl2 is a protective agent and a candidate target gene for therapy of muscle dystrophies.

cell biology↗

bioRxiv2023

Epigenomic perturbation of novel EGFR enhancers reduces the proliferative and invasive capacity of glioblastoma and increases sensitivity to temozolomide

Glioblastoma (GB) is the most aggressive of all primary brain tumours. Patients typically rely on radiotherapy with concurrent temozolomide (TMZ) treatment and face a median survival of [~]14 months. Alterations in the Epidermal Growth Factor Receptor gene (EGFR) are common in GB tumours, but therapies targeting EGFR have not shown significant clinical efficacy. Here, we investigated the influence of the EGFR regulatory genome on GB cells, and identified novel EGFR enhancers located in an intronic region nearby the GB-associated SNP rs723527. Epigenomic perturbation of this regulatory region using CRISPR-based methods decreases EGFR expression and reduces the proliferative and invasive capacity of glioblastoma cells, while increasing their sensitivity to TMZ. The enhancer-perturbed GB cells also undergo a metabolic reprogramming in favour of mitochondrial respiration and present increased apoptosis. Our findings demonstrate how epigenomic perturbation of EGFR enhancers can ameliorate the aggressiveness of glioblastoma cells and enhance the efficacy of TMZ treatment. SIGNIFICANCEOur study demonstrates how CRISPR/Cas9-based perturbation of enhancers can be used to modulate the expression of key cancer genes, which can help improve the effectiveness of existing cancer treatments and potentially the prognosis of difficult-to-treat cancers such as glioblastoma.

cancer biology↗

bioRxiv2023

Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice

Background & AimsThis study aimed to provide a comprehensive understanding of the regulatory and transcriptional landscape in liver tumours from DIAMOND mice, a mouse model that mimics human hepatocellular carcinoma (HCC) in the context of metabolic associated fatty liver disease (MAFLD). MethodsRNA-sequencing and ChIP-sequencing were used to study the gene expression and regulatory changes in DIAMOND liver tumours. RNA in situ hybridisation splice variant analysis was used to study {beta}-catenin exon 3 exclusion in tumours at cellular resolution. Sequencing data on {beta}-catenin exon 3 splicing in DIAMOND tumours was compared to data from human patients and cell lines. ResultsThe study found an increase in Wnt/{beta}-catenin-signalling accompanied by rewiring of the Wnt/{beta}-catenin regulatory network in DIAMOND tumours. Changes include switching in the expression of the canonical TCF/LEF downstream effectors and associated chromatin remodelling. In addition, a large subset of DIAMOND tumours showed aberrant splicing of {beta}-catenin, which generate an mRNA isoform that encodes an oncogenic protein. Similar splicing events were found in a fraction of human HCC and hepatoblastoma samples. ConclusionsThis study provides evidence that western diet induces aberrant genome-wide splicing in DIAMOND livers, and in particular of the {beta}-catenin gene in a subset of DIAMOND liver tumours. This mechanism is distinct from previously reported activation of {beta}-catenin in HCC and mouse models, since it is independent on mutations in the locus. Our data suggests that metabolic input modulates gene regulatory network responses to active Wnt-signalling, which will be an important consideration also in the human setting. Lay summarySequencing data generated in this study highlights the effect of diet in modulating oncogenic gene expression and underscores an alternative mutation-independent mechanism leading to constitutive activation of {beta}-catenin, a well-known driver of liver cancer.

cancer biology↗

bioRxiv2022

Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication

Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer pathogenesis. Here, we mapped the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks across the four glioblastoma subtypes. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodeling. SMAD3 and PITX1 emerge as the major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote cell proliferation of glioblastoma cells in co-culture with glutamatergic neurons. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.

genomics↗