Biology subjects

Mrabti, C.

Publications and source records attributed to Mrabti, C..

7 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↗

bioRxiv2023

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging.

Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via in vivo partial cellular reprogramming (IVPR) significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether epigenetic reprogramming can ameliorate DNA damage, we created reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in TGFb pathway is able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming.

cell biology↗

bioRxiv2022

ERCC1 mice, unlike other premature aging models, display accelerated epigenetic age

Over the last decades, several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (ERCC1, LAKI, POLG and XPG). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in ERCC1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. In line with these results, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight ERCC1 as a particularly attractive mouse model to study aging in mammals and suggest a strong connection between DNA damage and epigenetic dysregulation during aging.

molecular biology↗

bioRxiv2022

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan

The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that partial chemical reprogramming is able to improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical induced partial reprogramming, opening a path towards future translational applications.

cell biology↗

bioRxiv2022

In vivo reprogramming leads to premature death due to hepatic and intestinal failure.

SUMMARYThe induction of cellular reprogramming by forced expression of the transcription factors OCT4, SOX2, KLF4, and C-MYC (OSKM) has been shown to allow the dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. Yet to date, the benefits of in vivo reprogramming are limited by the occurrence of detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous in vivo induction of the reprogramming factors leads to hepatic and intestinal dysfunction resulting in decreased body weight and premature death. By generating a novel transgenic reprogrammable mouse strain, which avoids OSKM expression in both liver and intestine, we drastically reduced the early lethality and adverse effects associated with in vivo reprogramming. This new reprogramming mouse allows safe and long-term continuous induction of OSKM and might enable a better understanding of in vivo reprogramming as well as maximize its potential effects on rejuvenation and regeneration.

molecular biology↗