An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions
Abstract
:1. Introduction
1.1. Literature Search Strategy
1.2. Types of Epigenetic Modifications
- DNA Methylation:
- Histone Modifications:
- Non-coding RNAs (ncRNAs):
1.2.1. DNA Methylation
Protein Family | Family Members | Main Functions |
---|---|---|
DNMTs | DNMT1 DNMT3A DNMT3B | DNMT1 is the switch from neurogenesis to gliogenesis during NSC differentiation [35]. DNMT3A regulates NSC proliferation and differentiation [36] and controls adult hippocampal neurogenesis of GABAergic neurons [37]. DNMT3B is required for the proper timing of neuronal differentiation and maturation [38]. |
MBD proteins MBD1–5 2MeCP2 | MBD1 deficiency causes the accumulation of NSCs and the impairment of neuronal lineage differentiation [39,40,41] and contributes to the genesis of acute pain by epigenetic gene silencing in primary sensory neurons [42]. MBD2 and MBD3 are crucial for ESC differentiation to neural cells [43]. MBD4 intervenes in selective gene expression profiles in cortical neurons [44]. MBD5 controls neurite outgrowth and is responsible for 2Iq23.1 microdeletion syndrome [45]. 2MeCP2 controls neuronal maturation and dendritic arborization during development [46] and in the adult brain [47]. | |
MBPs | Zinc finger/Kaiso proteins Kaiso/ZBTB33 ZBTB4 ZBTB38 | Kaiso/ZBTB33 intervenes in the neuronal commitment of NSCs [48]. ZBTB4 controls gene expression in different types of neurons (hippocampus, olfactory pathways, motor nuclei of the brainstem, and granular layer of the cerebellum) [49] and is associated with age-at-onset AD [50]. ZBTB38 can repress transcription by binding to methylated DNA. It leads to early embryonic death via the suppression of the transcription factors Nanog and Sox2 [51]. |
SRA proteins UHRF1 UHRF2 | UHRF1 is critical for the maintenance of DNA methylation through cell division and is involved in DNA damage repair. It regulates the proliferation of NSCs [52]. UHRF2 is involved in cell cycle progression and controls the transition from RPCs to differentiated cells by regulating the cell cycle, epigenetic modifications, and gene expression [53]. |
1.2.2. Histone Epigenetic Modifications
Histone | Type of Modification | Residue(s) | Biological Effect |
---|---|---|---|
H1 | Su | K17, K21, K34 | Gene repression, chromatin compaction, and restriction of embryonic cell fate identity [72] |
H2A | Ac | K5 | Gene activation [73] |
P | S1 | Mitosis [74] | |
P | T120 | Mitosis, gene activation [27] | |
Su | K127 | Gene repression, chromatin compaction [75] | |
Ub | K119 | Gene repression [76] | |
H2AX | P | S139 | DNA repair [77] |
Su | K5, K9, K13, K15, K118, K119, K127, K133, K134 | Gene repression, chromatin compaction [78] | |
H2B | Ac | K5, K12, K15, K20 | Gene activation [79] |
P | S14 | Apoptosis [80,81] | |
Su | K16 | Gene repression, chromatin compaction [82] | |
Ub | K12 | Gene activation [83] | |
H3 | Ac | K4, K9, K14, K18, K23, K27, K36 | Gene activation [84] |
Ac | K56 | Histone deposition [85] | |
Cr | K9 | DNA repair [32] | |
Cr | K4, K14, K18, K27 | Gene activation [86] | |
La | K4, K18, K79 | Gene activation [30] | |
Me | K9, K27 | Gene repression [87] | |
Me | R2, R8, R17, R26 | Gene activation [88] | |
P | T6 | Gene activation [89] | |
P | S10, S28, T3, T11 | Mitosis, DNA repair [90,91] | |
P | T45 | DNA replication, response to DNA damage [92] | |
Ser | Q5 | Gene activation [93] | |
Su | K18 | Gene repression, chromatin compaction [94] | |
Ub | K23 | Maintenance of DNA methylation [95] | |
H4 | Me | R3 | Gene activation [96] |
P | S1 | Mitosis, gene activation [74] | |
Ac | K12, K91 | Histone deposition [97] | |
Ac | K5, K8, K12, K16 | Gene activation [98] | |
Me | K20 | Gene repression [99] | |
Su | K5, K8, K12, K16, K20 | Gene repression, chromatin compaction [100] |
1.2.3. ncRNAs
2. Epigenetic Regulation in the Developing and Mature Brain
Dynamic Regulation of Epigenetic Modifications in Response to Environmental Factors
3. Epigenetic Modifications in the Aging Brain
3.1. Contribution of Oxidative Stress to Epigenetic Changes in the Aging Brain
3.2. Contribution of Inflammation to Epigenetic Changes in the Aging Brain
3.3. Contribution of Mitochondrial Dysfunction to Epigenetic Changes in the Aging Brain
3.4. Other Factors Contributing to Epigenetic Changes in the Aging Brain
4. Histone Modifications and Brain Aging
5. Epigenetic Clocks and Their Relevance for Aging
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
List of Abbreviations
1 mA | 1-methyladenine |
2 MeCP2 | methyl-CpG-binding protein 2 |
3 mA | 3-methyladenine |
5 mC | 5-methylcytosine |
6 mA | N6-methyl deoxyadenosine |
AD | Alzheimer’s disease |
ASD | autism spectrum disorder |
BDNF | brain-derived neurotrophic factor |
CREB2 | cAMP response element binding protein 2 |
DNMT1 | DNA methyltransferase 1 |
DNMT3A | DNA methyltransferase 3A |
DNMT3B | DNA methyltransferase 3B |
DNMTs | DNA methyltransferases |
eRNAs | enhancer RNAs |
ESC | embryonic stem cells |
GATA3 | GATA binding protein 3 |
HAT | histone acetyltransferase |
HDACs | histone deacetylases |
HDACIs | histone deacetylase inhibitors |
hmC | 5-hydroxymethylcytosine |
HMT | histone methyltransferase |
IEGs | immediate early genes |
KDAC | lysine deacetylase |
KMT | histone lysine methyltransferase |
lncRNAs | long non-coding RNAs |
LTP | long-term potentiation |
MBPs | methyl-CpG binding proteins |
mCH | non-CG methylation |
MBD | methyl-binding domain |
MBD1–5 | Methyl-CpG-binding domain protein 1 to 5 |
mRNA | messenger RNA |
miRNAs | microRNAs |
NaB | sodium butyrate |
ncRNAs | non-coding RNAs |
NMDA | N-methyl-D-aspartate |
NSCs | neural stem cells |
PD | Parkinson’s disease |
piRNAs | PIWI-interacting RNAs |
pri-miRNA | hairpin-containing primary transcripts |
RGCs | radial glial cells |
ROS | reactive oxygen species |
RPCs | retinal precursor cells |
SA-gal | senescence-associated-galactosidase |
SASP | senescence-associated secretory phenotype |
siRNAs | small interfering RNAs |
SIRT1 | sirtuin 1 |
SRA | SET- and RING-associated domain proteins |
SUMO | small ubiquitin-like modifier |
TGM2 | transglutaminase 2 |
TNFα | tumor necrosis factor α |
TSA | trichostatin A |
UHRF1 | ubiquitin-like containing PHD ring finger 1 |
UHRF1 | ubiquitin-like containing PHD ring finger 1 |
ZBTB4 | zinc finger and BTB domain-containing protein 4 |
ZBTB33 | zinc finger and BTB domain-containing protein 33 |
ZBTB 38 | zinc finger and BTB domain-containing protein 38 |
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Epigenetic Mark | Biological Effects | Brain Region | Target |
---|---|---|---|
Reduction of H3K9ac | Lowered expression of key genes to neuronal and synaptic development Decrease in age-related memory and learning capacity | Hippocampus | IEGs [205] |
Reduction of H3K14ac | Hippocampus | IEGs [205] | |
Reduction of H3K27ac | Prefrontal cortex Hippocampus | GATA3, BDNF [146] | |
Reduction of H4K12ac | Hippocampus | Synaptic function-related genes [144] | |
Increase in H3K9me2 | Aging | Cerebral cortex Hippocampus | Excitatory neurons [206] |
Increase of H3K9me3 | Reduction in dendritic growth and stability | Cerebral cortex Hippocampus | BDNF [207] |
Memory deficit | Hippocampus | BDNF [208] IEGs [209] | |
Learning and memory ability decline | Brain tissue from AD patients and mouse models | Mitochondrial function-related genes [210] | |
Increase of H3K4me2 | Increased expression of related stress response proteins and inducing cognitive impairment | Prefrontal cortex | Stress-related genes [211] |
Increase of H3K27me3 | Activation of stress and immune inflammation | Brain | Stress-related genes [212,213] |
Reduction of H3K36me3 | Impaired memory function | Cerebral cortex Hippocampus | BDNF [214] |
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Lossi, L.; Castagna, C.; Merighi, A. An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions. Int. J. Mol. Sci. 2024, 25, 3881. https://doi.org/10.3390/ijms25073881
Lossi L, Castagna C, Merighi A. An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions. International Journal of Molecular Sciences. 2024; 25(7):3881. https://doi.org/10.3390/ijms25073881
Chicago/Turabian StyleLossi, Laura, Claudia Castagna, and Adalberto Merighi. 2024. "An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions" International Journal of Molecular Sciences 25, no. 7: 3881. https://doi.org/10.3390/ijms25073881