Biology subjects

Olieslagers, S.

Publications and source records attributed to Olieslagers, S..

3 recordsLinked to original sources

bioRxiv2023

LncRNA Bigheart trans-activates gene expression in a feed forward mechanism that facilitates calcineurin-NFAT signaling in myocardial hypertrophy

Terminally differentiated cardiomyocytes exhibit hypertrophy as a default response to injury by translating biomechanical stress into a complex network of intracellular signaling events. The molecular intricacies how calcium-dependent signaling engage molecular circuits and epigenetic modifications to activate deleterious gene programs remain enigmatic. Here we report on the re-activation of the evolutionarily conserved lncRNA "Bigheart", which is repressed in the postnatal myocardium and quickly re-activated in a calcineurin-NFAT-dependent fashion in the diseased myocardium in man and mouse. In line, AAV9-mediated overexpression of lncRNA Bigheart in otherwise healthy primary cardiomyocytes or mouse hearts suffices to drive maladapative hypertrophy. Conversely, mice receiving a "Gapmer" antisense oligonucleotide designed to specifically silence endogenous lncRNA Bigheart display resistance to biomechanical stress-induced myocardial remodeling, indicating its requirement in left ventricular hypertrophy. Mechanistically, lncRNA Bigheart recruits the RNA binding proteins hnRNP-F1 and HMGB1 to modulate the local chromatin environment and trans-activate Bigheart target genes including Rcan1 to stimulate calcineurin-NFAT coupling. Our observations confirm that human heart failure arises from specific susceptibilities in gene regulatory circuits that are amenable for therapeutic intervention using RNA-based therapeutics.

molecular biology↗

bioRxiv2021

A microRNA program controls the transition of cardiomyocyte hyperplasia to hypertrophy and stimulates mammalian cardiac regeneration

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b[~]25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b[~]25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b[~]25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b[~]25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b[~]25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.

molecular biology↗

bioRxiv2019

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

In the human, there is a circadian rhythm in the resting heart rate and it is higher during the day in preparation for physical activity. Conversely, slow heart rhythms (bradyarrhythmias) occur primarily at night. Although the lower heart rate at night is widely assumed to be neural in origin (the result of high vagal tone), the objective of the study was to test whether there is an intrinsic change in heart rate driven by a local circadian clock. In the mouse, there was a circadian rhythm in the heart rate in vivo in the conscious telemetrized animal, but there was also a circadian rhythm in the intrinsic heart rate in denervated preparations: the Langendorff-perfused heart and isolated sinus node. In the sinus node, experiments (qPCR and bioluminescence recordings in mice with a Per1 luciferase reporter) revealed functioning canonical clock genes, e.g. Bmal1 and Per1. We identified a circadian rhythm in the expression of key ion channels, notably the pacemaker channel Hcn4 (mRNA and protein) and the corresponding ionic current (funny current, measured by whole cell patch clamp in isolated sinus node cells). Block of funny current in the isolated sinus node abolished the circadian rhythm in the intrinsic heart rate. Incapacitating the local clock (by cardiac-specific knockout of Bmal1) abolished the normal circadian rhythm of Hcn4, funny current and the intrinsic heart rate. Chromatin immunoprecipitation demonstrated that Hcn4 is a transcriptional target of BMAL1 establishing a pathway by which the local clock can regulate heart rate. In conclusion, there is a circadian rhythm in the intrinsic heart rate as a result of a local circadian clock in the sinus node that drives rhythmic expression of Hcn4. The data reveal a novel regulator of heart rate and mechanistic insight into the occurrence of bradyarrhythmias at night.

physiology↗