Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells
Abstract
1. Introduction
2. Cellular Senescence: Mechanisms and Pathways
3. DNA Methylation Involved in Stem Cell Senescence
4. Histone Modification and Chromatin Remodeling Complexes Involved in Stem Cell Senescence
4.1. Histone Methylation
4.2. Histone Acetylation/Deacetylation
4.3. Histone Phosphorylation and Ubiquitination
4.4. Chromatin Remodeling Complexes
5. RNA Modification Involved in Stem Cell Senescence
5.1. m6A Modification
- “writer” m6A methyltransferases: METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429;
- “eraser” demethylases: FTO and ALKBH5;
- “reader” m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3, and HNRNPA2B1.
5.2. m5C Modification
5.3. Adenosine-to-Inosine (a-to-I) RNA Editing
5.4. Non-coding RNAs
5.4.1. miRNAs
5.4.2. LncRNAs
5.4.3. circRNAs
6. Animal Models of Senescence Research
7. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Enzyme/Factor | Role | Mouse Loss-of-Function Model | Human Diseases Due to Mutations |
---|---|---|---|
DNMT3A | De novo DNA methyltransferase |
|
|
DNMT3B | De novo DNA methyltransferase |
|
|
DNMT3C | De novo DNA methyltransferase (mice/rats specific isoform) |
| |
DNMT3L | DNA methyltransferase cofactor |
| |
DNMT1 | Maintenance DNA methyltransferase |
|
|
UHFR1 | DNMT1 cofactor |
| |
TET1 | DNA demethylation via oxidation of methylcytosine |
| |
TET2 | DNA demethylation via oxidation of methylcytosine |
|
|
TET3 | DNA demethylation via oxidation of methylcytosine |
|
Histone Deacetylase | ||||
---|---|---|---|---|
Classification | Localization | Inhibitors (Examples) | ||
Zn+ dependent | Class I | HDAC 1 HDAC 2 HDAC 3 HDAC 8 | Mainly nucleus Nucleus Nucleus/cytoplasm Mainly cytoplasm | Benzamides (MS-275, MCGD0103, CI-994) Cyclic peptide (Depsipeptide, Apicidin) Aliphatic fatty acids (butyrate, valproic acid) Hydroxamate (SAHA, PXD100, LBH589, 4SC-201, Tubacin, ITF2357, PCI2478I) Mercaptoketone (KD5170) |
Class II | HDAC 4 HDAC 5 HDAC 6 HDAC 7 HDAC 9 HDAC 10 | Nucleus/cytoplasm Nucleus/cytoplasm Cytoplasm Nucleus/cytoplasm/ mitochondria Nucleus/cytoplasm Nucleus/cytoplasm | Aliphatic fatty acids (butyrate, valproic acid) Hydroxamate (SAHA, PXD100, LBH589, 4SC-201, Tubacin, ITF2357, PCI2478I) Mercaptoketone (KD5170) | |
Class IV | HDAC 11 | Mainly nucleus | Hydroxamate (SAHA, PXD100, IFT2357, 4SC-201) | |
NAD+ dependent | Class III | SIRT 1 SIRT 2 SIRT 3 SIRT 4 SIRT 5 SIRT 6 SIRT 7 | Cytoplasm Cytoplasm/nucleus Mitochondria Mitochondria Mitochondria Nucleus Nucleus | Hydroxamate (SAHA, PXD100, IFT2357, 4SC-201) Benzamides (MCGD0103 |
Histone Acetyltransferase | ||||
Classification | Localization | Inhibitors (Eexamples, * Nonselective) | ||
Zn+ dependent | Cytoplasmic | KAT1 (HAT1) HAT4 (NAA60) HAT2 HATB3.1 Rtt109 | Cytoplasm | *Anacardic acid *Isothiazolones |
GNAT (bromodomain) | KAT2A (Gcn5) KAT2B (PCAF) ELP3 | Nucleus | Ischemin Ischemin *Anacardic acid *Isothiazolones | |
MYST (acetyl-CoA motif) | KAT5 (TIP60) KAT6A (MOZ, MYST3) KAT6B (MORF, MYST4) KAT7 (HBO1, MYST2) KAT8 (MOF, MYST1) | Nucleus | TH1834 *Anacardic acid *Isothiazolones | |
NAD+ dependent | P300/CBP | KAT3B (p300) KAT3A (CBP) | Nucleus | Garcinol, curcumin, benzylidene barbituric acid, C646, CTPB, TTk21 TTK21, ICG-001, ischemin |
Transcription co-activators | KAT4 (TAF1, TBP) KAT12 (TIFIIIC90) | Nucleus | *Anacardic acid *Isothiazolones | |
Steroid receptor co-activators | KAT13A (SRC1) KAT13B (SCR3, ACTR) KAT13C (p600) KAT13D (CLOCK) | Nucleus | *Anacardic acid *Isothiazolones |
Epigenetic Modification | Substrate | Enzymes/Target | Senescence |
---|---|---|---|
DNA methylation DNA demethylation | CpG sites | DNMT3A, DNMT3B, DMNT1 | ↑ |
TET1, TET2, TET3 | ↓ | ||
Histone methylation | H3K4me3 | KDM5A, ASH1L | ↑ |
H3K9m2/3 | JMJD-1.2/PHF8, JMJD-3.1/JMJD3 | ↓ | |
H3K23me3 | JMJD-1.2/PHF8, JMJD-3.1/JMJD3 | ↓ | |
H3K27me3 | JMJD-1.2/PHF8, JMJD-3.1/JMJD3 | ↓ | |
H3K27me3 | EZH2 | ↑ | |
H3K36me2/3 | SETD2 | ↑ | |
H3R2/17/26me | CARM1data | ↑ | |
Histone acetylation | H3K9ac | SIRT6 | ↓ |
H3K56ac | SIRT6 | ↓ | |
K3K27ac | HDAC4 | ↑ | |
H3K14ac | KAT7 | ↑ | |
H3K9ac | GCN5 (KAT2A) | ↑ | |
H3K9ac | PCAF (KAT2B) | ↑ | |
Histone phosphorylation | H3S10p | Aurora kinase | ↑ |
H3T11p | CK2 | ↑ | |
H3S28p | in Drosophila cells | ↓ | |
γH2AX | ATM, ATR | ↑ | |
Histone ubiquitination | H2Bub | BRCA1/BARD1; E3 ligase | ↑ |
H2Aub | BRCA1/BARD1; E3 ligase | ↑ | |
Chromatin remodeling complex | SWI/SNF | ARID1B/ENTPD7 | ↑ |
NuRD | HDAC1 | ↑ | |
RNA modifications | m6A m5C A-to-I RNA editing | methyltransferases: METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429 demethylases: FTO and ALKBH5 tRNA methyltransferase NSUN2 ADAR1, ADAR2 | ↑ ↑ ↑ ↓ |
miRNA | mir17 family miR-195 miR-486-5p, miR-204 miR-495 miR-141-3p, miR-543, miR-590-3p miR-543, miR-590-3p miR-141 osteogenic markers miR-188 miR-21 miR-146-5p miR-34a miR-106b family, miR-130b, miR-302a, miR-302b, miR-302c, miR-302d, miR-512-3p, and miR-515-3p | p12 SIRT1, TERT BMI1 ZMPSTE24 AIMP3/p18 SVCT2, DF-1 Frizzled-4 MAP3K3 E2F2 TNFα p53 p21 | ↓ ↓ ↑ ↑ ↑ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↓ |
LncRNA | NEAT1 APTR LncHSC-1, LncHSC-2 ANRIL GAS5 GUARDIN H19 HCP5 | CSF1 Dnmt3a p53 -p21 pathway NAMPT, PI3K/AKT pathway PGC1α and LRP130 p16 -p21 pathway, miR-22 miR-128 | ↑ ↓ ↓ ↓ ↑ ↑ ↓ ↑ |
circRNA | circRNA-0077930 | KRAS, p21, p53, p16, miR-622 | ↑ |
circ-Foxo3 | ID-1, E2F1, FAK, HIF1α | ↑ | |
circLARP4 | miR-761/RUNX3 axis | ↑ | |
circPVT1 | let-7 | ↓ | |
circCCNB1 | CCNE2, miR-449a | ↓ | |
circACTA2 | ILF3, CDK4 | ↑ | |
▬ methyltransferase ▬ demethylase ▬ histone deacetylase ▬ histone acetyltransferase |
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Iordache, F.; Petcu, A.C.I.; Alexandru, D.M. Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells. Int. J. Mol. Sci. 2024, 25, 9708. https://doi.org/10.3390/ijms25179708
Iordache F, Petcu ACI, Alexandru DM. Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells. International Journal of Molecular Sciences. 2024; 25(17):9708. https://doi.org/10.3390/ijms25179708
Chicago/Turabian StyleIordache, Florin, Adriana Cornelia Ionescu Petcu, and Diana Mihaela Alexandru. 2024. "Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells" International Journal of Molecular Sciences 25, no. 17: 9708. https://doi.org/10.3390/ijms25179708
APA StyleIordache, F., Petcu, A. C. I., & Alexandru, D. M. (2024). Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells. International Journal of Molecular Sciences, 25(17), 9708. https://doi.org/10.3390/ijms25179708