TRIM37 (nanisme Mulibrey) : implication dans le cycle cellulaire et régulation post-transcriptionnelle par le miR-223 dans les chondrocytes

TRIM37 fait partie de la famille des protéines TRIM qui possèdent toutes des domaines RING, B-box et Coiled coil. TRIM37 s'individualise par la présence d'un domaine spécifique MATH localisé dans la partie C-terminale. Le syndrome Mulibrey (dit aussi nanisme primordial) est la conséquence de mutations dans TRIM37. Les syndromes de nanisme ont pour origine principale des anomalies du cartilage de conjugaison (acteur majeur de la croissance des os longs) composé de chondrocytes. En utilisant les techniques de l'imagerie confocale et de la cytométrie en flux suivie d'analyses d'images (ImageStream) nous montrons que TRIM37 est exprimé à la fois dans le cytoplasme et le noyau des chondrocytes et que cette expression est maximale en phase mitotique. Par ailleurs, nous montrons l'association de TRIM37 avec l'alpha-tubuline pendant la mitose et faisant partie intégrante du fuseau mitotique. Selon nos résultats, la déplétion de TRIM37 entraine une diminution de la prolifération des chondrocytes alors qu'à l'inverse, sa surexpression entraîne une augmentation de la prolifération cellulaire. Nous mettons aussi en évidence une régulation post transcriptionnelle de TRIM37 par le miR-223 dans les chondrocytes. Les travaux de protéomique et de transcriptomique nous apprennent que lors de la sous expression de TRIM37 dans la lignée CHON-002, l'expression des protéines spécifiques de la matrice extra-cellulaire est augmentée. En particulier la protéine SPARC semble être un partenaire privilégié de TRIM37. Nos résultats soulignent la participation de TRIM37 aux phénomènes de croissance osseuse. Tous ces résultats pourraient avoir un impact sur la thérapie des troubles liés aux nanismesTRIM37 is a member of the tripartite motif (TRIM) protein family, which contains a RING/BBox coiled coil domain and a MATH domain localized in the C-terminal region. Mutations in the TRIM37 gene cause the Mulibrey nanism, a heritable growth disorder. Since chondrocytes are instrumental in long bone growth that is deficient in nanism, we hypothesized that TRIM37 defect could cause a default in the chondrocyte cell cycle regulation. Western blotting, confocal microscopy and imaging flow cytometry determined TRIM37 expression in CHON-002 cell lineage. During the chondrocyte cell cycle, TRIM37 was present in both nucleus and cytoplasm. Moreover, TRIM37 co-localized with alpha-tubulin only during mitosis. TRIM37 Knock Down inhibits proliferation, while overexpression accordingly increases it. Finally, we demonstrate that the microRNA-223, involved in bone remodeling, directly targets TRIM37, and suggest that miR-223 regulates TRIM37 gene expression during the cell cycle. Proteomics and Transciptomics studies suggest that TRIM37 KD enhance matrix specific protein expression. Furthermore, SPARC has been identified as a major molecular partner of TRIM37. In summary, our results give clues to explain why TRIM37 deficiency in chondrocytes impacts bone growth. Modulating TRIM37 using miR-223 could be an approach that can be implemented to increase chondrogenesi

TRIMming down to TRIM37: Relevance to Inflammation, Cardiovascular Disorders, and Cancer in MULIBREY Nanism

International audienceTRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the MULIBREY (MUscle-LIver-BRain-EYe) genetic disorder caused by TRIM37 mutations. TRIM37 is characterized by the presence of a RING domain, B-box motifs, and a coiled-coil region, and its C-terminal part includes the MATH domain specific to TRIM37. MULIBREY nanism is a rare autosomal recessive caused by TRIM37 mutations and characterized by severe pre- and postnatal growth failure. Constrictive pericarditis is the most serious anomaly of the disease and is present in about 20% of patients. The patients have a deregulation of glucose and lipid metabolism, including type 2 diabetes, fatty liver, and hypertension. Puzzlingly, MULIBREY patients, deficient for TRIM37, are plagued with numerous tumors. Among non-MULIBREY patients affected by cancer, a wide variety of cancers are associated with an overexpression of TRIM37. This suggests that normal cells need an optimal equilibrium in TRIM37 expression. Finding a way to keep that balance could lead to potential innovative drugs for MULIBREY nanism, including heart condition and carcinogenesis treatment

miR-92a: A Novel Potential Biomarker of Rapid Aortic Valve Calcification

International audienceBackground and aim of the study: The study aim wasto compare the tissular expression of microRNAs(miRs) in bicuspid and tricuspid valves, and to evaluate their use as potential novel biomarkers of aortic valve calcification in bicuspid valves. Methods: A prospective single-center observational study was conducted on stenotic bicuspid andtricuspid human aortic valves. According to their potential role in valve vascular and valvular calcification, a decision was taken to include miR-92a, miR-141, and miR-223 in this analysis. A real-time quantitative polymerase chain reaction was used to measure the expression of each miR, using U6and Cel-miR-39 as endogenous and exogenous genecontrols, respectively. Results: Among a total of 47 human calcified aortic valves collected, 30 (63.8%) were tricuspid valves. Theme an preoperative transvalvular gradient was 50.8mmHg (range: 37-89 mmHg), with no significant difference between bicuspid and tricuspid valves(50 mmHg versus 51.2 mmHg; p = 0.729). Theme an aortic valve area was 0.79 cm2 (range: 0.33-1.3 cm2), again with no significant difference between the two groups (p = 0.34). The level of miR-92a expression was twofold higher in bicuspid valves compared to tricuspid valves (0.38 versus 0.17; p = 0.016), butno significant difference in miR-141 and miR-223 expression was observed between the two groups (p =0.68 and p = 0.35, respectively). A positive correlation was observed between miR-92a expression and mean preoperative transvalvular gradient (r = 0.3257, p =0.04). Conclusion: miR-92a is overexpressed in calcified bicuspid aortic valves, and may serve as a potential biomarker of rapid aortic valve calcification. Further studies based on these results may be designed to correlate the relative expression of miR-92a in the serum with its tissular expression in AS

Serum microRNAs are altered in various stages of chronic kidney disease: a preliminary study

International audienceBackground: MicroRNAs (miRNAs) are innovative and informative blood-based biomarkers involved in numerous pathophysiological processes. In this study and based on our previous experimental data, we investigated miR-126, miR-143, miR-145, miR-155 and miR-223 as potential circulating biomarkers for the diagnosis and prognosis of patients with chronic kidney disease (CKD). The primary objective of this study was to assess the levels of miRNA expression at various stages of CKD.Methods: RNA was extracted from serum, and RT-qPCR was performed for the five miRNAs and cel-miR-39 (internal control).Results: Serum levels of miR-143, -145 and -223 were elevated in patients with CKD compared with healthy controls. They were further increased in chronic haemodialysis patients, but were below control levels in renal transplant recipients. In contrast, circulating levels of miR-126 and miR-155 levels, which were also elevated in CKD patients, were lower in the haemodialysis group and even lower in the transplant group. Four of the five miRNA species were correlated with estimated glomerular filtration rate, and three were correlated with circulating uraemic toxins.Conclusions: This exploratory study suggests that specific miRNAs could be biomarkers for complications of CKD, justifying further studies to link changes of miRNA levels with outcomes in CKD patients

RETRACTION: Serum microRNAs are altered in various stages of chronic kidney disease: a preliminary study (Retraction of Vol 10, Pg 30, 2017)

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Syndecan-1 and Free Indoxyl Sulfate Levels Are Associated with miR-126 in Chronic Kidney Disease

International audienceChronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and its blood level is decreased in CKD patients. In order to obtain a better understanding of the physiopathology of the disease, we correlated the levels of miR-126 with several markers of endothelial dysfunction, as well as the representative uremic toxins, in a large cohort of CKD patients at all stages of the disease. Using a univariate analysis, we found a correlation between eGFR and most markers of endothelial dysfunction markers evaluated in this study. An association of miR-126 with all the evaluated uremic toxins was also found, while uremic toxins were not associated with the internal control, specifically cel-miR-39. The correlation between the expression of endothelial dysfunction biomarker Syndecan-1, free indoxyl sulfate, and total p-cresyl glucuronide on one side, and miR-126 on the other side was confirmed using multivariate analysis. As CKD is associated with reduced endothelial glycocalyx (eGC), our results justify further evaluation of the role of correlated parameters in the pathophysiology of CKD

Serum levels of miR-126 and miR-223 and outcomes in chronic kidney disease patients.

Several microRNAs (miRNAs) have been linked to chronic kidney disease (CKD) mortality, cardiovascular (CV) complications and kidney disease progression. However, their association with clinical outcomes remains poorly evaluated. We used real-time qPCR to measure serum levels of miR-126 and miR-223 in a large cohort of 601 CKD patients (CKD stage G1 to G5 patients or on renal replacement therapy - CKD G5D) from Ghent University Hospital and 31 healthy controls. All-cause mortality and cardiovascular and renal events were registered as endpoints over a 6 year follow-up period. miR-126 levels were significantly lower from CKD stage G2 on, compared to controls. The serum levels of miR-223 were significantly lower from CKD stage G3B on. When considering overall mortality, patients with levels of either miR-126 or miR-223 below the median had a lower survival rate. Similar results were observed for CV and renal events. The observed link between the two miRNAs' seric levels and mortality, cardiovascular events or renal events in CKD appears to depend on eGFR. However, this does not preclude their potential role in the pathophysiology of CKD. In conclusion, CKD is associated with a decrease in circulating miR-223 and miR-126 levels.status: Published onlin

Geomstats: A Python Package for Riemannian Geometry in Machine Learning

We introduce Geomstats, an open-source Python toolbox for computations and statistics on nonlinear manifolds, such as hyperbolic spaces, spaces of symmetric positive definite matrices, Lie groups of transformations, and many more. We provide object-oriented and extensively unit-tested implementations. Among others, manifolds come equipped with families of Riemannian metrics, with associated exponential and logarithmic maps, geodesics and parallel transport. Statistics and learning algorithms provide methods for estimation, clustering and dimension reduction on manifolds. All associated operations are vectorized for batch computation and provide support for different execution backends, namely NumPy, PyTorch and TensorFlow, enabling GPU acceleration. This paper presents the package, compares it with related libraries and provides relevant code examples. We show that Geomstats provides reliable building blocks to foster research in differential geometry and statistics, and to democratize the use of Riemannian geometry in machine learning applications. The source code is freely available under the MIT license at http://geomstats.ai.Idex UCA JEDI3IA Côte d'AzurG-Statistics - Foundations of Geometric Statistics and Their Application in the Life Science

Introduction to Geometric Learning in Python with Geomstats

International audienceThere is a growing interest in leveraging differential geometry in the machine learning community. Yet, the adoption of the associated geometric computations has been inhibited by the lack of a reference implementation. Such an implementation should typically allow its users: (i) to get intuition on concepts from differential geometry through a hands-on approach, often not provided by traditional textbooks; and (ii) to run geometric machine learning algorithms seamlessly, without delving into the mathematical details. To address this gap, we present the open-source Python package geomstats and introduce hands-on tutorials for differential geometry and geometric machine learning algorithms-Geometric Learning-that rely on it. Code and documentation: github.com/geomstats/geomstats and geomstats.ai