Biology subjects

Trembley, M.

Publications and source records attributed to Trembley, M..

4 recordsLinked to original sources

bioRxiv2025

Mechanisms of Cardiomyocyte Aging

Aging is a major risk factor for cardiovascular diseases, yet the underlying molecular mechanisms remain poorly understood. In this study, we integrated physiological characterization of cardiomyocyte (CM) aging with concurrent single-nucleus RNA-seq and ATAC-seq, and reduced representation bisulfite sequencing to delineate the cellular and molecular landscape of CM aging in mice. Our analysis revealed significant age-associated changes in CM physiology, including hypertrophy, fibrosis, and diastolic dysfunction. We uncovered dramatic epigenetic remodeling in aged CMs, characterized by increased chromatin accessibility and altered DNA methylation patterns. Overexpression of the DNA methylase DNMT3A in young adult mouse hearts recapitulated key features of the aged heart phenotype, establishing DNA hypermethylation as a significant regulator of age-related CM function. Furthermore, ESRRG, an orphan nuclear receptor, functions as a mediator of diastolic function in the heart. Its overexpression significantly improved diastolic function and reduced expression of a non-coding RNA that is upregulated in aged CMs. These novel insights into the molecular mechanisms underlying cardiac aging identify molecular regulators involved in age-associated cardiac remodeling.

molecular biology↗

bioRxiv2025

Lipopolysaccharides nanodiscs, a biomimetic platform to study bacterial surface.

Lipopolysaccharides (LPS) are essential components of the outer membranes of Gram-negative bacteria, playing a crucial role in antimicrobial resistance, virulence, and the hosts immune response. Self-assembled particles displaying LPS are essential for biophysical studies addressing the behavior of bacterial surfaces under specific biomimetic conditions. Styrene-maleic acid (SMA) copolymers were employed to form LPS nanodiscs, either from extracted LPS or directly from purified outer membranes. These nanodiscs, derived from pathogenic O157:H7 or laboratory E. coli strains, are well-defined in size and yield high-resolution nuclear magnetic resonance (NMR) spectra. They have been successfully used to investigate molecular recognition by a human C-type Lectin Receptor (CLR) of the immune system and interaction with polymyxin antibiotics using various biophysical methods. This study high-lights the significance of LPS nanodiscs as bacterial surface mimetics and opens promising avenues for further research into LPS structure and interactions. The ability to generate well-defined LPS nanodiscs offers a powerful tool for studying the molecular mechanisms underlying bacterial pathogenesis and immune response.

biophysics↗

bioRxiv2021

RBPMS2 is a conserved regulator of alternative splicing that promotes myofibrillar organization and optimal calcium handling in cardiomyocytes

RationaleThe identification of novel cardiomyocyte-intrinsic factors that support heart function will expand the number of candidate genes and therapeutic options for heart failure, a leading cause of death worldwide. ObjectiveTo identify and characterize conserved regulators of cardiomyocyte function. Methods and ResultsWe report that the RNA-binding protein RBPMS2 is required for myofibril organization and the regulation of intracellular calcium dynamics in both zebrafish embryos and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). A differential expression screen in zebrafish uncovered enrichment of rbpms2 paralogs, rbpms2a and rbpms2b, in the myocardium. Double knock-out (rbpms2-null) embryos suffer from compromised ventricular filling during the relaxation phase of the cardiac cycle, which significantly reduces cardiac output. Whole transcriptome sequencing and validation studies revealed differential alternative splicing of several genes linked to cardiomyopathies in humans, including myosin binding protein C3 (mybpc3) and phospholamban (pln), consistent with a role in causing the observed ventricular deficiencies. Further, RBPMS2-null hiPSC-CMs exhibit myofibril and calcium handling defects that are highly analogous to those observed in the rbpms2-null zebrafish ventricle. ConclusionsTaken together, our data identify RBPMS2 as a conserved and essential regulator of alternative splicing that is required for myofibrillar organization and optimal calcium handling from zebrafish to humans.

developmental biology↗

bioRxiv2019

Sarcomeres regulate cardiomyocyte maturation through MRTF-SRF signaling

Cardiomyocyte maturation is essential for robust heart contraction throughout life. The signaling networks governing cardiomyocyte maturation remain poorly defined. Our prior studies established the transcription factor SRF as a key regulator of the assembly of sarcomeres, the contractile unit of cardiomyocytes. Whether sarcomeres regulate other aspects of maturation remains unclear. Here we generated mice with cardiomyocyte specific, mosaic mutation of -actinin-2 (Actn2), a key organizer of sarcomeres, to study its cell-autonomous role in cardiomyocyte maturation. In addition to the expected structural defects, Actn2 mutation triggered dramatic transcriptional dysregulation, which strongly correlated with transcriptional changes observed in SRF-depleted cardiomyocytes. Actn2 mutation increased monomeric actin, which perturbed the nuclear localization of the SRF cofactor MRTFA. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the transcriptional and morphological defects in Actn2 and Srf mutant cardiomyocytes. Together, we demonstrate that ACTN2-based sarcomere assembly and MRTF-SRF signaling establish a positive feedback loop that promotes cardiomyocyte maturation.

developmental biology↗