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Review
. 2024 Sep 7;25(17):9708.
doi: 10.3390/ijms25179708.

Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells

Florin Iordache  1   2 , Adriana Cornelia Ionescu Petcu  1 , Diana Mihaela Alexandru  3
Affiliations
Review

Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells

Florin Iordache et al. Int J Mol Sci. .

Abstract

Cellular senescence is a permanent condition of cell cycle arrest caused by a progressive shortening of telomeres defined as replicative senescence. Stem cells may also undergo an accelerated senescence response known as premature senescence, distinct from telomere shortening, as a response to different stress agents. Various treatment protocols have been developed based on epigenetic changes in cells throughout senescence, using different drugs and antioxidants, senolytic vaccines, or the reprogramming of somatic senescent cells using Yamanaka factors. Even with all the recent advancements, it is still unknown how different epigenetic modifications interact with genetic profiles and how other factors such as microbiota physiological conditions, psychological states, and diet influence the interaction between genetic and epigenetic pathways. The aim of this review is to highlight the new epigenetic modifications that are involved in stem cell senescence. Here, we review recent senescence-related epigenetic alterations such as DNA methylation, chromatin remodeling, histone modification, RNA modification, and non-coding RNA regulation outlining new possible targets for the therapy of aging-related diseases. The advantages and disadvantages of the animal models used in the study of cellular senescence are also briefly presented.

Keywords: acetylation; cellular senescence; epigenetics; histone; methylation; stem cells.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Cellular and molecular modification that promote senescence and strategies aim to alleviate senescence.
Figure 2
Figure 2
DNA methylation mechanism at the promoter level. (a) DNA methylation at promoters: trimethylated histone H3 Lys4 (H3K4me3) prevents binding to chromatin of the ADD domain of DNMT3A and DNMT3B (and of DNMT3L). These interactions cause it to bind to the methyltransferase (MTase) domain and auto-inhibit the DNMT3 enzymes. (b) In the absence of H3K4 methylation, the ADD domain binds to H3K4 and the auto-inhibition is relieved, thereby allowing the MTase domain to methylate the DNA. (c) In gene bodies, the ADD domain binds unmethylated H3K4, thereby releasing the auto-inhibition of the DNMT3 enzymes. H3K36me3 is deposited in the gene bodies of actively transcribed genes and serves as a recruitment module for the DNMT3 PWWP domain.
Figure 3
Figure 3
DNA methylation mechanism at replication level. UHRF1 is recruited to replicate DNA through SRA domain, and binds hemimethylated CpG sites. The TTD domain binds H3K9me2. The RING domain of UHRF1 ubiquitylates the histone H3 (Ub). The replication foci-targeting sequence (RFTS) of DNMT1 folds into the MTase domain, thereby preventing its catalytic activity. UHRF1 enrolls DNMT1 through an interaction between its ubiquitin-like (UBL) domain and the DNMT1 RFTS. Auto-inhibition of DNMT1 is released when the RFTS binds to ubiquitylated H3 tails, which enables the maintenance of symmetrical DNA methylation at CpG sites.
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