Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma

Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ

SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains

Mechanisms of gene repression by transforming growth factor-beta (TGF-beta) are not well understood. TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function. In comparison, weaker interaction of FOXA1 winged helix, and the NH2-terminal domains was documented with SMAD3. Both in vitro studies and in vivo ChIP assays show that interaction of SMAD3 MH1 and MH2 domains with NKX2.1 and FOXA1 results in reduced binding of NKX2.1 and FOXA1 to their cognate DNA-binding sites, and diminished promoter occupancy within the SpB promoter. Thus, these studies reveal for the first time a mechanism of TGF-beta-induced SpB gene repression that involves interactions between specific SMAD3 domains and the corresponding functional sites on NKX2.1 and FOXA1 transcription factors

Transcriptomic research in atherosclerosis: Unravelling plaque phenotype and overcoming methodological challenges

Atherosclerotic disease is a major cause of acute cardiovascular events. A deeper understanding of its underlying mechanisms will allow advancing personalized and patient-centered healthcare. Transcriptomic research has proven to be a powerful tool for unravelling the complex molecular pathways that drive atherosclerosis. However, low reproducibility of research findings and lack of standardization of procedures pose significant challenges in this field. In this review, we discuss how transcriptomic research can help in understanding the different phenotypes of the atherosclerotic plaque that contribute to the development and progression of atherosclerosis. We highlight the methodological challenges that need to be addressed to improve research outputs, and emphasize the importance of research protocols harmonization. We also discuss recent advances in transcriptomic research, including bulk or single-cell sequencing, and their added value in plaque phenotyping. Finally, we explore how integrated multiomics data and machine learning improve understanding of atherosclerosis and provide directions for future research

The science behind soft skills: Do’s and Don’ts for early career researchers and beyond. A review paper from the EU-CardioRNA COST Action CA17129

peer reviewedSoft skills are the elementary management, personal, and interpersonal abilities that are vital for an individual to be efficient at workplace or in their personal life. Each work place requires different set of soft skills. Thus, in addition to scientific/technical skills that are easier to access within a short time frame, several key soft skills are essential for the success of a researcher in today’s international work environment. In this paper, the trainees and trainers of the EU-CardioRNA COST Action CA17129 training school on soft skills present basic and advanced soft skills for early career researchers. Here, we particularly emphasize on the importance of transferable and presentation skills, ethics, literature reading and reviewing, research protocol and grant writing, networking, and career opportunities for researchers. All these skills are vital but are often overlooked by some scholars. We also provide tips to ace in aforementioned skills that are crucial in a day-to-day life of early and late career researchers in academia and industry.</ns4:p

Catalyzing Transcriptomics Research in Cardiovascular Disease : The CardioRNA COST Action CA17129

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu)

Defects in High Density Lipoprotein metabolism and hepatic steatosis in mice with liver-specific ablation of Hepatocyte Nuclear Factor 4A

BACKGROUND Aberrant concentration, structure and functionality of High Density Lipoprotein (HDL) are associated with many prevalent diseases, including cardiovascular disease and non-alcoholic fatty liver disease (NAFLD). Mice with liver-specific ablation of Hnf4α (H4LivKO) present steatosis and dyslipidemia by mechanisms that are not completely understood. The aim of this study was to explore the role of liver HNF4A in HDL metabolism and the development of steatosis. METHODS AND RESULTS Serum and tissue samples were obtained from 6-weeks old H4LivKO mice and their littermate controls. Liver and serum lipids were measured and HDL structure and functionality were assessed. Global gene expression changes in the liver were analyzed by expression arrays, validations were performed by RT-qPCR and DNA-protein interactions were studied by chromatin immunoprecipitation (ChIP). H4LivKO mice presented liver steatosis, increased liver triglyceride content and decreased concentration of serum total cholesterol, HDL cholesterol, triglycerides, phospholipids and cholesteryl esters. Most classes of phospholipids showed significant changes in species ratio and sphingosine-1-phosphate (S1P) levels were reduced. H4LivKO serum was enriched in the smaller, denser HDL particles, devoid of APOA2 and APOM apolipoproteins, exhibiting decreased activity of paraoxonase-1 but retaining macrophage cholesterol efflux capacity and phospho-AKT activation in endothelial cells. Global gene expression analysis revealed the association of liver HNF4A with known and novel regulators of HDL metabolism as well as NAFLD-susceptibility genes. CONCLUSIONS HNF4A ablation in mouse liver causes hepatic steatosis, perturbations in HDL structure and function and significant global changes in gene expression. This study reveals new targets of HNF4A involved in HDL metabolism and the development of steatosis and enriches our knowledge on HDL functionality in NAFLD