Biology subjects

Isern, J.

Publications and source records attributed to Isern, J..

4 recordsLinked to original sources

bioRxiv2025

Titin cleavage is a driver of cardiomyocyte disengagement and reactive myocardial fibrosis

Myocardial remodeling including cardiomyocyte-death-independent, reactive fibrosis and disconnection of cardiomyocytes is at the basis of prevalent cardiac conditions converging into arrhythmias and heart failure. However, the molecular mechanisms behind these pathogenic responses remain incompletely understood limiting therapeutic opportunities. Here, we find that a molecular event common to unrelated heart diseases, namely the cleavage of the sarcomeric protein titin, is enough to trigger fast myocardial remodeling. Using an engineered system based on the expression of tobacco etch virus protease (TEVp) in mice, we show that 30% mosaic cardiac titin cleavage leads to global cardiomyocyte disengagement, activation of cardiac fibroblasts and interstitial collagen deposition. These effects are concurrent, involve ERK1/2 signaling, and are expected to contribute, at least, to myocardial remodeling in chemotherapy-induced cardiotoxicity and ischemia damage.

physiology↗

bioRxiv2021

Cell transcriptomic atlas of the non-human primate Macaca fascicularis

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP.

cell biology↗

bioRxiv2020

mRNA translation control by Dhx36 binding to 5' UTR G-quadruplex structures is essential for skeletal muscle stem cell regenerative functions

Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells, also called satellite cells (SCs), that are normally quiescent. When stimulated by damage, SCs activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that Dhx36, a helicase that unwinds RNA quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. We find that Dhx36 (initially named RHAU) is barely expressed at quiescence and is highly induced during SC activation and proliferation. Inducible deletion of Dhx36 in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs revealed Dhx36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling showed that Dhx36 promotes mRNA translation via 5UTR rG4 binding. Furthermore, we demonstrate that Dhx36 specifically regulates the translation of Gnai2 mRNA by unwinding its 5UTR rG4 structures and identify Gnai2 as a downstream effector of Dhx36 for SC expansion. Altogether our findings uncover Dhx36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration through binding and unwinding rG4 structures at 5UTR of target mRNAs.

cell biology↗

bioRxiv2020

In-vivo Transcriptomic Profiling of Systemic Aging using Cell Encapsulation

Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy.

bioengineering↗