Role of HDAC5 Epigenetics in Chronic Craniofacial Neuropathic Pain
Abstract
:1. Introduction
2. Effect of LMK235 Post-Treatment on Behavioral Hypersensitivity, TG Electrophysiological Response, and Molecular Profile in a Chronic Trigeminal Neuropathic Pain Model
3. Effects of Class IIa HDACi LMK235 on Craniofacial Nerve Injury Hypersensitivity
4. Electrophysiological Responses of TG to LMK235
5. Molecular Profile Alterations with Trigeminal Nerve Injury and LMK235 Treatment
6. Corroboration of the Molecular Profile with Behavioral and TG Electrophysiological Responses
6.1. KCNE2
6.2. P2X4R and P2X7R
6.3. CCKBR
6.4. Somatostatin
7. Effects on Anxiety- and Depression-Like Behaviors
8. Epigenetic Dysregulation and Genes Differentially Regulated in Chronic Craniofacial Pain
9. How RNA Alterations Are Associated with Improvements in Trigeminal Nerve In-Jury Models
10. Anti-Inflammation
11. Axonal Repair
12. Other Molecular and Epigenetic Mechanisms Implicated
13. Pituitary Hormone with Nociceptive Actions
14. Epigenetic Balance
15. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Mouse Genes Up- and Down-Regulated Also Reported in Human Trigeminal Neuralgia | FRICT-ION Vs. Naïve | LMK235-Treated FRICT-ION Vs. Naïve | LMK235-Treated FRICT-ION Vs. Untreated FRICT-ION | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Gene Symbol | NAME | Fold-Change | 2-Value | FDR | Fold-Change | p-Value | FDR | Fold-Change | p-Value | FDR |
Arfgef2 | ADP-ribosylation factor guanine nucleotide-exchange factor 2 (brefeldin A-inhibited) | 1.01 | 8.02 × 10−1 | 9.38 × 10−1 | 1.02 | 6.82 × 10−1 | 9.30 × 10−1 | 1.01 | 8.74 × 10−1 | 9.65 × 10−1 |
Astn2 | astrotactin 2 | −1.02 | 7.72 × 10−1 | 9.26 × 10−1 | 1.04 | 5.61 × 10−1 | 8.87 × 10−1 | 1.06 | 3.80 × 10−1 | 7.47 × 10−1 |
Bmp2 | bone morphogenetic protein 2 | 1.13 | 3.27 × 10−1 | 6.66 × 10−1 | 1.11 | 4.04 × 10−1 | 8.21 × 10−1 | −1.02 | 8.75 × 10−1 | 9.65 × 10−1 |
Bmp3 | bone morphogenetic protein 3 | 2.20 | 1.57 × 10−3 | 2.81 × 10−2 | −1.23 | 4.34 × 10−1 | 8.35 × 10−1 | −2.70 | 7.00 × 10−5 | 4.66 × 10−3 |
Bmp4 | bone morphogenetic protein 4 | 1.13 | 5.55 × 10−1 | 8.28 × 10−1 | 1.18 | 4.15 × 10−1 | 8.27 × 10−1 | 1.05 | 8.23 × 10−1 | 9.50 × 10−1 |
Bmp5 | bone morphogenetic protein 5 | 1.87 | 2.02 × 10−2 | 1.54 × 10−1 | 1.85 | 2.16 × 10−2 | 4.22 × 10−1 | −1.01 | 9.64 × 10−1 | 9.89 × 10−1 |
Cacna1a | calcium channel; voltage-dependent; P/Q type; alpha 1A subunit | 1.10 | 6.89 × 10−2 | 3.15 × 10−1 | −1.06 | 2.67 × 10−1 | 7.47 × 10−1 | −1.16 | 3.24 × 10−3 | 6.64 × 10−2 |
Cacna1d | calcium channel; voltage-dependent; L type; alpha 1D subunit | 1.01 | 8.68 × 10−1 | 9.59 × 10−1 | −1.03 | 7.06 × 10−1 | 9.36 × 10−1 | −1.04 | 5.84 × 10−1 | 8.58 × 10−1 |
Cacna1g | calcium channel; voltage-dependent; T type; alpha 1G subunit | 1.42 | 3.73 × 10−4 | 9.63 × 10−3 | −1.00 | 9.71 × 10−1 | 9.95 × 10−1 | −1.43 | 3.12 × 10−4 | 1.38 × 10−2 |
Cacna1h | calcium channel; voltage-dependent; T type; alpha 1H subunit | 1.34 | 1.91 × 10−3 | 3.17 × 10−2 | −1.11 | 2.69 × 10−1 | 7.48 × 10−1 | −1.49 | 2.21 × 10−5 | 2.07 × 10−3 |
Cacna1i | calcium channel; voltage-dependent; alpha 1I subunit | 1.21 | 6.55 × 10−3 | 7.32 × 10−2 | −1.14 | 6.20 × 10−2 | 5.50 × 10−1 | −1.39 | 4.03 × 10−6 | 6.44 × 10−4 |
Cacnb1 | calcium channel; voltage-dependent; beta 1 subunit | 1.11 | 3.79 × 10−2 | 2.24 × 10−1 | −1.02 | 6.74 × 10−1 | 9.28 × 10−1 | −1.13 | 1.13 × 10−2 | 1.41 × 10−1 |
Clcn1 | chloride channel 1 | −1.27 | 2.53 × 10−1 | 5.99 × 10−1 | −1.33 | 1.67 × 10−1 | 6.68 × 10−1 | −1.05 | 8.20 × 10−1 | 9.49 × 10−1 |
Clcn2 | chloride channel 2 | −1.12 | 8.61 × 10−2 | 3.54 × 10−1 | −1.11 | 1.11 × 10−1 | 6.26 × 10−1 | 1.01 | 8.92 × 10−1 | 9.69 × 10−1 |
Clic5 | chloride intracellular channel 5 | −1.03 | 7.54 × 10−1 | 9.18 × 10−1 | −1.08 | 4.43 × 10−1 | 8.40 × 10−1 | −1.05 | 6.50 × 10−1 | 8.86 × 10−1 |
Eef2 | eukaryotic translation elongation factor 2 | −1.06 | 3.53 × 10−1 | 6.89 × 10−1 | −1.05 | 4.62 × 10−1 | 8.50 × 10−1 | 1.01 | 8.47 × 10−1 | 9.58 × 10−1 |
Gabra5 | gamma-aminobutyric acid (GABA) A receptor; subunit alpha 5 | 1.26 | 1.75 × 10−4 | 5.70 × 10−3 | 1.02 | 7.71 × 10−1 | 9.53 × 10−1 | −1.23 | 4.81 × 10−4 | 1.88 × 10−2 |
Gabra6 | gamma-aminobutyric acid (GABA) A receptor; subunit alpha 6 | −1.77 | 2.14 × 10−1 | 5.55 × 10−1 | 1.18 | 7.11 × 10−1 | 9.38 × 10−1 | 2.08 | 1.08 × 10−1 | 4.53 × 10−1 |
Gabre | gamma-aminobutyric acid (GABA) A receptor; subunit epsilon | −1.33 | 1.16 × 10−1 | 4.12 × 10−1 | −1.22 | 2.73 × 10−1 | 7.50 × 10−1 | 1.10 | 6.13 × 10−1 | 8.71 × 10−1 |
Gabrg1 | gamma-aminobutyric acid (GABA) A receptor; subunit gamma 1 | 1.11 | 2.41 × 10−1 | 5.86 × 10−1 | 1.26 | 7.39 × 10−3 | 3.41 × 10−1 | 1.14 | 1.31 × 10−1 | 4.93 × 10−1 |
Jakmip1 | janus kinase and microtubule interacting protein 1 | 1.12 | 3.13 × 10−2 | 2.00 × 10−1 | 1.02 | 7.51 × 10−1 | 9.47 × 10−1 | −1.10 | 6.08 × 10−2 | 3.44 × 10−1 |
Kcna5 | potassium voltage-gated channel; shaker-related subfamily; member 5 | 1.33 | 4.39 × 10−2 | 2.42 × 10−1 | −1.06 | 6.70 × 10−1 | 9.27 × 10−1 | −1.41 | 1.33 × 10−2 | 1.56 × 10−1 |
Kcnc3 | potassium voltage gated channel; Shaw-related subfamily; member 3 | −1.01 | 7.82 × 10−1 | 9.31 × 10−1 | −1.05 | 3.14 × 10−1 | 7.75 × 10−1 | −1.04 | 4.65 × 10−1 | 8.01 × 10−1 |
Kcnd2 | potassium voltage-gated channel; Shal-related family; member 2 | 1.09 | 8.36 × 10−2 | 3.47 × 10−1 | 1.09 | 9.02 × 10−2 | 5.93 × 10−1 | −1.00 | 9.66 × 10−1 | 9.90 × 10−1 |
Kcnh2 | potassium voltage-gated channel; subfamily H (eag-related); member 2 | −1.01 | 7.51 × 10−1 | 9.17 × 10−1 | −1.06 | 1.81 × 10−1 | 6.81 × 10−1 | −1.04 | 3.06 × 10−1 | 6.85 × 10−1 |
Kcnh7 | potassium voltage-gated channel; subfamily H (eag-related); member 7 | 1.23 | 1.87 × 10−1 | 5.21 × 10−1 | 1.03 | 8.65 × 10−1 | 9.73 × 10−1 | −1.19 | 2.36 × 10−1 | 6.29 × 10−1 |
Kcnj6 | potassium inwardly-rectifying channel; subfamily J; member 6 | 1.26 | 1.19 × 10−1 | 4.18 × 10−1 | −1.10 | 5.37 × 10−1 | 8.80 × 10−1 | −1.38 | 2.75 × 10−2 | 2.33 × 10−1 |
Kcnk1 | potassium channel; subfamily K; member 1 | −1.07 | 1.67 × 10−1 | 4.93 × 10−1 | −1.02 | 7.50 × 10−1 | 9.47 × 10−1 | 1.05 | 2.82 × 10−1 | 6.67 × 10−1 |
Kcns2 | K+ voltage-gated channel; subfamily S; 2 | 1.40 | 5.66 × 10−3 | 6.63 × 10−2 | 1.12 | 3.62 × 10−1 | 7.99 × 10−1 | −1.25 | 5.91 × 10−2 | 3.40 × 10−1 |
Kcnv1 | potassium channel; subfamily V; member 1 | 1.16 | 4.56 × 10−1 | 7.64 × 10−1 | 1.26 | 2.23 × 10−1 | 7.14 × 10−1 | 1.09 | 6.37 × 10−1 | 8.81 × 10−1 |
Kif1b | kinesin family member 1B | −1.00 | 9.89 × 10−1 | 9.97 × 10−1 | 1.01 | 8.81 × 10−1 | 9.76 × 10−1 | 1.01 | 8.69 × 10−1 | 9.64 × 10−1 |
Maoa | monoamine oxidase A | −1.06 | 1.96 × 10−1 | 5.33 × 10−1 | 1.08 | 9.03 × 10−2 | 5.93 × 10−1 | 1.14 | 2.64 × 10−3 | 5.76 × 10−2 |
Mapk3 | mitogen-activated protein kinase 3 | −1.02 | 6.05 × 10−1 | 8.52 × 10−1 | −1.02 | 5.92 × 10−1 | 9.00 × 10−1 | −1.00 | 9.87 × 10−1 | 9.96 × 10−1 |
Mpz | myelin protein zero | 1.13 | 8.73 × 10−1 | 9.61 × 10−1 | 1.07 | 9.25 × 10−1 | 9.85 × 10−1 | −1.05 | 9.47 × 10−1 | 9.85 × 10−1 |
Nacc2 | nucleus accumbens associated 2; BEN and BTB (POZ) domain containing | −1.05 | 2.73 × 10−1 | 6.19 × 10−1 | −1.05 | 2.68 × 10−1 | 7.48 × 10−1 | −1.00 | 9.92 × 10−1 | 9.97 × 10−1 |
Nav3 | neuron navigator 3 | 1.33 | 5.07 × 10−4 | 1.21 × 10−2 | 1.12 | 1.87 × 10−1 | 6.85 × 10−1 | −1.19 | 2.68 × 10−2 | 2.29 × 10−1 |
Ncald | neurocalcin delta | 1.01 | 6.84 × 10−1 | 8.89 × 10−1 | 1.05 | 1.74 × 10−1 | 6.75 × 10−1 | 1.03 | 3.41 × 10−1 | 7.16 × 10−1 |
Ndnf | neuron-derived neurotrophic factor | 1.24 | 2.98 × 10−2 | 1.95 × 10−1 | 1.31 | 5.67 × 10−3 | 3.29 × 10−1 | 1.06 | 5.55 × 10−1 | 8.48 × 10−1 |
Net1 | neuroepithelial cell transforming gene 1 | −1.24 | 9.15 × 10−3 | 9.20 × 10−2 | −1.11 | 2.12 × 10−1 | 7.07 × 10−1 | 1.12 | 1.68 × 10−1 | 5.46 × 10−1 |
Neurod4 | neurogenic differentiation 4 | −1.78 | 6.79 × 10−2 | 3.13 × 10−1 | −1.13 | 6.76 × 10−1 | 9.29 × 10−1 | 1.57 | 1.47 × 10−1 | 5.16 × 10−1 |
Nf2 | neurofibromatosis 2 | −1.06 | 5.82 × 10−2 | 2.87 × 10−1 | −1.02 | 4.86 × 10−1 | 8.60 × 10−1 | 1.04 | 2.22 × 10−1 | 6.12 × 10−1 |
Nfasc | neurofascin | −1.07 | 1.40 × 10−1 | 4.55 × 10−1 | −1.09 | 6.15 × 10−2 | 5.50 × 10−1 | −1.02 | 6.94 × 10−1 | 9.06 × 10−1 |
Ngef | neuronal guanine nucleotide exchange factor | 1.26 | 9.49 × 10−5 | 3.66 × 10−3 | −1.06 | 3.13 × 10−1 | 7.75 × 10−1 | −1.34 | 7.33 × 10−7 | 1.68 × 10−4 |
Nkain2 | Na+/K+ transporting ATPase interacting 2 | 1.20 | 8.88 × 10−3 | 9.05 × 10−2 | 1.05 | 4.84 × 10−1 | 8.59 × 10−1 | −1.14 | 5.34 × 10−2 | 3.22 × 10−1 |
Nova1 | neuro-oncological ventral antigen 1 | −1.00 | 9.95 × 10−1 | 9.99 × 10−1 | 1.04 | 3.05 × 10−1 | 7.68 × 10−1 | 1.04 | 3.01 × 10−1 | 6.81 × 10−1 |
Nras | neuroblastoma ras oncogene | 1.03 | 5.55 × 10−1 | 8.28 × 10−1 | −1.00 | 9.66 × 10−1 | 9.94 × 10−1 | −1.03 | 5.21 × 10−1 | 8.31 × 10−1 |
Nrep | neuronal regeneration related protein | 1.03 | 4.81 × 10−1 | 7.83 × 10−1 | 1.04 | 2.79 × 10−1 | 7.54 × 10−1 | 1.01 | 7.07 × 10−1 | 9.11 × 10−1 |
Nrg2 | neuregulin 2 | −1.06 | 6.54 × 10−1 | 8.74 × 10−1 | 1.04 | 7.24 × 10−1 | 9.41 × 10−1 | 1.10 | 4.16 × 10−1 | 7.71 × 10−1 |
Nrg3 | neuregulin 3 | 1.09 | 1.55 × 10−1 | 4.76 × 10−1 | 1.09 | 1.60 × 10−1 | 6.66 × 10−1 | −1.00 | 9.77 × 10−1 | 9.93 × 10−1 |
Nrp2 | neuropilin 2 | 1.00 | 9.64 × 10−1 | 9.90 × 10−1 | 1.07 | 3.21 × 10−1 | 7.79 × 10−1 | 1.07 | 3.41 × 10−1 | 7.16 × 10−1 |
Ntrk1 | neurotrophic tyrosine kinase; receptor; type 1 | −1.95 | 1.89 × 10−4 | 6.02 × 10−3 | −1.09 | 6.17 × 10−1 | 9.10 × 10−1 | 1.80 | 9.90 × 10−4 | 3.13 × 10−2 |
Nts | neurotensin | 2.05 | 2.09 × 10−10 | 1.29 × 10−7 | 1.18 | 1.60 × 10−1 | 6.66 × 10−1 | −1.74 | 4.23 × 10−7 | 1.16 × 10−4 |
Plcl1 | phospholipase C-like 1 | −1.00 | 9.54 × 10−1 | 9.87 × 10−1 | 1.12 | 4.57 × 10−2 | 5.13 × 10−1 | 1.13 | 3.94 × 10−2 | 2.78 × 10−1 |
Scn2a1 | sodium channel; voltage-gated; type II; alpha 1 | 1.15 | 2.10 × 10−3 | 3.37 × 10−2 | 1.10 | 2.62 × 10−2 | 4.41 × 10−1 | −1.04 | 3.85 × 10−1 | 7.51 × 10−1 |
Scn3a | sodium channel; voltage-gated; type III; alpha | 1.12 | 1.51 × 10−1 | 4.71 × 10−1 | 1.11 | 1.82 × 10−1 | 6.82 × 10−1 | −1.01 | 9.15 × 10−1 | 9.76 × 10−1 |
Scn5a | sodium channel; voltage-gated; type V; alpha | 1.23 | 2.78 × 10−1 | 6.24 × 10−1 | 1.23 | 2.59 × 10−1 | 7.41 × 10−1 | 1.01 | 9.76 × 10−1 | 9.93 × 10−1 |
Scn7a | sodium channel; voltage-gated; type VII; alpha | 1.15 | 3.32 × 10−1 | 6.71 × 10−1 | 1.07 | 6.19 × 10−1 | 9.10 × 10−1 | −1.07 | 6.29 × 10−1 | 8.78 × 10−1 |
Scn8a | sodium channel; voltage-gated; type VIII; alpha | −1.12 | 2.49 × 10−3 | 3.80 × 10−2 | −1.07 | 8.10 × 10−2 | 5.76 × 10−1 | 1.05 | 1.98 × 10−1 | 5.85 × 10−1 |
Scn9a | sodium channel; voltage-gated; type IX; alpha | −1.28 | 7.02 × 10−4 | 1.54 × 10−2 | 1.01 | 8.54 × 10−1 | 9.73 × 10−1 | 1.29 | 2.62 × 10−4 | 1.21 × 10−2 |
Slc6a4 | solute carrier family 6 (neurotransmitter transporter; serotonin); member 4 | −4.86 | 4.23 × 10−6 | 3.07 × 10−4 | −1.11 | 7.48 × 10−1 | 9.47 × 10−1 | 4.38 | 1.56 × 10−5 | 1.55 × 10−3 |
Trak1 | trafficking protein; kinesin binding 1 | −1.04 | 2.17 × 10−1 | 5.57 × 10−1 | −1.05 | 1.11 × 10−1 | 6.26 × 10−1 | −1.01 | 7.24 × 10−1 | 9.16 × 10−1 |
Trpc6 | transient receptor potential cation channel; subfamily C; member 6 | −1.17 | 3.27 × 10−1 | 6.66 × 10−1 | −1.08 | 6.16 × 10−1 | 9.10 × 10−1 | 1.08 | 6.17 × 10−1 | 8.73 × 10−1 |
Trpm2 | transient receptor potential cation channel; subfamily M; member 2 | −1.08 | 1.00 × 10−1 | 3.83 × 10−1 | −1.10 | 3.87 × 10−2 | 4.85 × 10−1 | −1.02 | 6.78 × 10−1 | 9.00 × 10−1 |
Trpm3 | transient receptor potential cation channel; subfamily M; member 3 | −1.07 | 4.08 × 10−1 | 7.33 × 10−1 | 1.12 | 1.57 × 10−1 | 6.66 × 10−1 | 1.19 | 2.47 × 10−1 | 2.19 × 10−1 |
Trpm4 | transient receptor potential cation channel; subfamily M; member 4 | −1.19 | 1.12 × 10−1 | 4.06 × 10−1 | −1.14 | 2.32 × 10−1 | 7.18 × 10−1 | 1.05 | 6.82 × 10−1 | 9.02 × 10−1 |
Trpm7 | transient receptor potential cation channel; subfamily M; member 7 | 1.04 | 3.95 × 10−1 | 7.22 × 10−1 | 1.10 | 5.15 × 10−2 | 5.27 × 10−1 | 1.06 | 2.72 × 10−1 | 6.59 × 10−1 |
Trps1 | trichorhinophalangeal syndrome I (human) | 1.11 | 1.13 × 10−1 | 4.06 × 10−1 | 1.14 | 3.61 × 10−2 | 4.81 × 10−1 | 1.03 | 6.17 × 10−1 | 8.73 × 10−1 |
Trpv4 | transient receptor potential cation channel; subfamily V; member 4 | 1.76 | 3.27 × 10−1 | 6.66 × 10−1 | 2.12 | 1.91 × 10−1 | 6.87 × 10−1 | 1.21 | 7.37 × 10−1 | 9.21 × 10−1 |
Trpv6 | transient receptor potential cation channel; subfamily V; member 6 | 1.10 | 6.11 × 10−1 | 8.54 × 10−1 | −1.07 | 7.19 × 10−1 | 9.40 × 10−1 | −1.19 | 3.74 × 10−1 | 7.42 × 10−1 |
Unc80 | unc−80 homolog (C. elegans) | −1.03 | 5.86 × 10−1 | 8.44 × 10−1 | 1.07 | 1.84 × 10−1 | 6.84 × 10−1 | 1.10 | 6.07 × 10−2 | 3.44 × 10−1 |
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Hui, S.E.; Westlund, K.N. Role of HDAC5 Epigenetics in Chronic Craniofacial Neuropathic Pain. Int. J. Mol. Sci. 2024, 25, 6889. https://doi.org/10.3390/ijms25136889
Hui SE, Westlund KN. Role of HDAC5 Epigenetics in Chronic Craniofacial Neuropathic Pain. International Journal of Molecular Sciences. 2024; 25(13):6889. https://doi.org/10.3390/ijms25136889
Chicago/Turabian StyleHui, Sifong Elise, and Karin N. Westlund. 2024. "Role of HDAC5 Epigenetics in Chronic Craniofacial Neuropathic Pain" International Journal of Molecular Sciences 25, no. 13: 6889. https://doi.org/10.3390/ijms25136889