Biology subjects

Yacoub Maroun, C.

Publications and source records attributed to Yacoub Maroun, C..

3 recordsLinked to original sources

bioRxiv2024

Loss of H3K9 trimethylation leads to premature aging

Aging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process. Modifications in transcriptional networks and chromatin structure might be central to age-related functional decline. A prevalent feature described during aging is the overall reduction in heterochromatin, specifically marked by the loss of repressive histone modification, Histone 3 lysine 9 trimethylation (H3K9me3). However, the role of H3K9me3 in aging, especially in mammals, remains unclear. Here we show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit reduced lifespan, lower body weight, increased frailty index, multi-organ degeneration, transcriptional changes with significant upregulation of transposable elements, and accelerated epigenetic age. Our data strongly supports the concept that the loss of epigenetic information directly drives the aging process. These findings reveal the importance of epigenetic regulation in aging and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline. Understanding the molecular mechanisms underlying the process of aging will be crucial for developing novel therapeutic strategies that can delay the onset of age-associated diseases and preserve human health at old age specially in rapidly aging societies.

physiology↗

bioRxiv2024

Neuron-specific partial reprogramming in the dentate gyrus impacts mouse behavior and ameliorates age-related decline in memory and learning.

Age-associated neurodegenerative disorders represent significant challenges due to progressive neuronal decline and limited treatments. In aged mice, partial reprogramming, characterized by pulsed expression of reprogramming factors, has shown promise in improving function in various tissues, but its impact on the aging brain remains poorly understood. Here we investigated the impact of in vivo partial reprogramming on mature neurons in the dentate gyrus of young and aged mice. Using two different approaches - a neuron-specific transgenic reprogrammable mouse model and neuron-specific targeted lentiviral delivery of OSKM reprogramming factors - we demonstrated that in vivo partial reprogramming of mature neurons in the dentate gyrus, a neurogenic niche in the adult mouse brain, can influence animal behavior, and ameliorate age-related decline in memory and learning. These findings underscore the potential of in vivo partial reprogramming as an important therapeutic intervention to rejuvenate the neurogenic niche and ameliorate cognitive decline associated with aging or neurodegeneration.

neuroscience↗

bioRxiv2024

Comparative analysis of mouse strains for in vivo reprogramming

In vivo reprogramming through the forced expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) has demonstrated great potential for reversing age-associated phenotypes, as the combination of these transcription factors actively promote cell regeneration and rejuvenation in various tissues and organs. However, continuous in vivo OSKM expression raised safety concerns due to loss of cell identity, decrease in body weight, and premature death. Although cyclic short-term or targeted expression of the reprogramming factors can mitigate some of these detrimental effects in mice, systemic rejuvenation of wild type mice has remained elusive potentially due to these current technical limitations. To improve the fundamental understanding of in vivo reprogramming, we conducted a comparative analysis across multiple reprogrammable mouse strains, tissues, and expression methods, presenting a comprehensive atlas of formerly established strains. In addition, we developed novel reprogrammable mouse strains by avoiding OSKM expression in specific organs, in dividing cells, or implementing chimeric expression approaches within specific cells, thereby offering safer strategies to induce in vivo reprogramming and fully harness its potential. We hope that these new tools will become valuable resources for future research in this very exciting field of research with potential implications to human health.

molecular biology↗