Table 3.
List of epigenetic marks and their roles during OPC differentiation.
| DNA Modification | Enzyme/Mark | Role | Targeted Genes or Functions | Model | Methods | References |
|---|---|---|---|---|---|---|
| DNA methylation | DNMT1 | Positive role in OPC differentiation | In vitro OPCs + siRNA | Egawa et al. [132] | ||
| Negative role in OPC differentiation and myelination | Decreased DNA methylation and upregulation of lipid synthesis and myelin formation genes (Mog, Mag, Gpr37) | Olig1cre;Dnmt1flox mice (no phenotype in Cnpcre;Dnmt1flox mice) | RNA-Seq and ERRBS on sorted neonatal OPCs and OLs, RNA-Seq on sorted Olig1cre;Dnmt1flox OPCs | Moyon et al. [91] | ||
| DNMT1/DNMT3A | Positive role in OPC differentiation and remyelination | PlpcreRT;Dnmt1flox;Dnmt3flox mice | Moyon et al. [142] | |||
| DNA hydroxymethylation | TET1/TET2/TET3 | Positive role in OPC differentiation | In vitro OPCs + siRNAs | Zhao et al. [35] | ||
| TET1 | Positive role in OPC differentiation and (re)myelination (no role for TET3) | Activation of cell differentiation genes (Mag) | Olig1cre;Tet1flox mice | hMeDIP-Seq on in vitro neonatal NSCs and OPCs, RNA-Seq on in vitro Olig1cre;Tet1flox OPCs | Zhang et al. [92] | |
| Positive role in OPC differentiation and adult remyelination only (no role for TET2) | Activation of cell differentiation, myelination, biosynthesis and neuroglial communication genes (Slc family members, Pcdh family members) | Olig1cre;Tet1flox and PdgfracreRT;Tet1flox mice | RNA-Seq and RRHP on sorted adult OPCs and OLs, RNA-Seq on oligo-enriched Olig1cre;Tet1flox lesioned spinal cord | Moyon et al. [133] | ||
| Histone Modification | Enzyme/Mark | Role | Targeted Genes or Functions | Model | Methods | References |
| Histone methylation | PRC2 (EED) (H3K27me3) | Negative role in OPC differentiation and (re)myelination | Chromatin silencing of differentiation genes (Bmp, Wnt) | Olig1cre;Eedflox, Plpcre-Eedflox and PdgfracreRT;Eedflox mice | RNA-Seq and ChIP-Seq on in vitro Olig1cre;Eedflox OPCs | Wang et al. [96] |
| H3K9me3 | Positive role in OPC differentiation (no role for H3K27me3) | In vitro OPCs and OLs | ChIP-Seq on in vitro OPCs and Ols | Liu et al. [97] | ||
| KMT2/MLL (H3K4me3) | Positive role in OPC differentiation | Recruited by CHD8, mark accumulation at promoters of differentiation genes (Tcf7l2, Myrf, Zfp488, Lnc-OL1) | Olig1cre;Chd8flox mice + KDM5 demethylase inhibitors | ChIP-Seq on in vitro Olig1cre;Chd8flox OPCs | Zhao et al. [138] | |
| PRMT5 | Positive role in OPC differentiation and myelination | Regulation of OPC differentiation genes | Olig1cre;Prmt5flox mice and in vitro OPCs + siRNA | RNA-Seq on in vitro PRMT5-CRISPRKO OPCs | Scaglione et al. [134] | |
| Positive role in OPC differentiation and myelination | Regulation of OPC differentiation genes | Olig2cre;Prmt5flox mice | RNA-Seq on Olig2cre;Prmt5flox brain | Calabretta et al. [154] | ||
| Positive role in OPC differentiation | Repression of inhibitors of differentiation (Id2/4) | In vitro OPCs and glioma cells + siRNA | Huang et al. [155] | |||
| Histone deacetylation | HDACs | Positive role in OPC differentiation | In vitro O4+ cells + HDAC inhibitors | Conway et al. [136] | ||
| In vitro OPCs + HDAC inhibitors | Marin-Husstege et al. [143] | |||||
| Positive role in OPC differentiation and myelination | In vivo HDAC inhibitors | Shen et al. [156] | ||||
| Positive role in OPC differentiation and remyelination | Shen et al. [157] | |||||
| HDAC1/HDAC2 | Positive role in OPC differentiation and myelination | Olig1cre;Hdac1flox;Hdac2flox mice | Ye et al. [121] | |||
| HDAC1 | Positive role in OPC differentiation | In vitro OPCs + siRNA | Egawa et al. [132] | |||
| HDAC2 | Negative role in OPC differentiation | |||||
| HDAC6 | Positive role in OPC differentiation and OL morphology | Deacetylation of alpha-tubulin | In vitro OPCs + siRNA | Noack et al. [158] | ||
| HDAC11 | Positive role in OPC differentiation | In vitro Olineu cells + siRNA | Liu et al. [159] | |||
| SIRT2 | Negative role in OPC differentiation | Deacetylation of alpha-tubulin | In vitro Olineu cells + siRNA | Li et al. [160] | ||
| Histone citrullination | PADI2 | Positive role in OPC differentiation | Activation of cell differentiation genes (Septins, Mbp, Sox9/10, Tcf7l2) (+ role on non-histone targets, e.g., myelin proteins) | PdgfracreRT;Padi2flox mice, in vitro OPCs + siRNA, in vitro Olineu + overexpression | Proteomic and ATAC-Seq on in vitro OPCs + siRNA | Falcão et al. [55] |
| Chromatin Organization | Enzyme/Mark | Role | Targeted Genes or Functions | Model | Methods | References |
| Chromatin remodelers | CHD7 | Positive role in OPC differentiation and (re)myelination | Transcriptional activation of differentiation genes (Sox10, Gpr17, Sirt2, Nkx2.2) | PdgfracreRT;Chd7flox mice | RNA-Seq on in vitro PdgfracreRT;Chd7flox OPCs | Marie et al. [61] |
| PdgfracreRT;Chd7flox mice | Doi et al. [137] | |||||
| Transcriptional activation of differentiation genes (Myrf, Sox10) | Olig1cre;Chd7flox mice | RNA-Seq on Olig1cre;Chd7flox spinal cord | He et al. [59] | |||
| CHD8 | Positive role in OPC differentiation and (re)myelination | Transcriptional activation of differentiation genes (Tcf7l2, Myrf, Zfp488, Lnc-OL1) | Olig1cre;Chd8flox and PdgfracreRT;Chd8flox mice | ChIP-Seq and ATAC-Seq on in vitro Olig1cre;Chd8flox OPCs | Zhao et al. [138] | |
| BRG1 | Positive role in OPC differentiation and myelination | Transcriptional activation of differentiation genes (Myrf, Sox10) | Olig1cre;Brg1flox mice | RNA-Seq and ChIP-Seq on Olig1cre;Brg1flox optic nerve | Yu et al. [62] | |
| Cnpcre;Brg1flox mice | Bischof et al. [57] | |||||
| EP400 | Positive role in OPC differentiation | Transcriptional activation of differentiation genes (Plp1, Mbp, Mog, Myrf, Sox10) | Cnpcre;Ep400flox mice | ChIP-Seq on sorted Cnpcre;Ep400flox OPCs | Elsesser et al. [139] | |
| Nuclear lamina | LMNB1 | Negative role in OPC differentiation | Repression of differentiation genes (cholesterol synthesis, Lss) | In vitro OPCs + LMNB1 overexpression | DamID on in vitro OPCs, combining with LMNB1 maintained expression | Yattah et al. [68] |
| Post-Transcriptional Modification | Enzyme/Mark | Role | Targeted Genes or Functions | Model | Methods | References |
| Long non-coding RNA | lnc-OL1 | Positive role in OPC differentiation and (re)myelination | Silencing of OPC program during their differentiation (interaction with SUZ12, within PRC2) | In vitro OPCs + lnc-OL1 overexpression and Ezh2 siRNA, Olig1cre;Ezh2flox mice | He et al. [161] | |
| Neat1 | Positive role in OPC differentiation | Over-representation of oligodendroglial pathways among differentially expressed genes | Neat1−/− mice | RNA-Seq of Neat1−/− mouse brains | Katsel et al. [115] | |
| lnc-158 | Positive role in OPC differentiation | In vitro NSCs + lnc-158 overexpression and siRNA | Li et al. [113] | |||
| MicroRNA | DICER | Positive role in OPC differentiation and myelination | Olig2cre;Dicerflox and Cnpcre;Dicerflox mice | Dugas et al. [162] | ||
| Positive role in myelination | Olig1cre;Dicerflox mice | Zhao et al. [140] | ||||
| miR-219 | Positive role in OPC differentiation | Repression of inhibitors of differentiation (Zfp238, Foxj3) | In vitro OPCs + miR-219 overexpression | Dugas et al. [162] | ||
| miR-338 | Positive role in OPC differentiation | Repression of inhibitors of differentiation (Sox6, Hes5) | In vitro OPCs + miR-219 overexpression, in vivo electroporation in chicks and zebrafish | Zhao et al. [140] | ||
| miR-23 | Positive role in OPC differentiation and myelination | Upregulation of myelin genes (Cnp, Plp1, Mag, Mog) and downregulation of OPC and nuclear lamina genes (Pdgfra, Lmnb1) | In vivo miR-23 overexpression in CNP+ cells (mouse model) | RNA-Seq | Lin et al. [163] | |
| miR-32 | Positive role in OPC differentiation | Promotes expression of myelin proteins and glucose/lipi metabolism (MBP, SLC45A3) | In vitro OPCs + miR-32 overexpression and shRNA | Shin et al. [164] | ||
| miR-27a | Negative role in OPC differentiation and (re)myelination | Targets mature OL-specific genes (Mbp) | In vitro OPCs + miR-27a overexpression, ex vivo inhibition in cerebellum slices, in vivo intranasal inhibition in mice | RNA-Seq | Tripathi et al. [165] | |
| miR-212 | Negative role in OPC differentiation | Inhibition of oligodendroglial genes (Mbp, Olig1/2, Sox10) | In vitro OPCs + miR-212 overexpression and siRNA | Validation by rtqPCR | Wang et al. [166] | |
| miR-125-3p | Negative role in OPC differentiation | Inhibition of differentiation genes (Fyn, Smad4, Nrg1) | In vitro OPCs + miR-125-3p overexpression and siRNA | Validation by rtqPCR | Lecca et al. [167] | |
| m6A RNA methylation | METTL14 | Positive role in OPC differentiation | Necessary for mature myelin gene expression (Mbp, Mog, Mag, Plp1, Cnp) and regulation of histone modification enzymes (HATs, HMTs, HDACs, KDMs) | Olig2cre;Mettl14flox and Cnpcre;Mettl14flox mice | RNA-Seq on in vitro Olig2cre;Mettl14flox OPCs | Xu et al. [168] |
| FTO | Positive role in OPC differentiation and myelination | Promotes Olig2 degradation | Fto-TG mice | RNA-Seq on Nescre;Prrc2aflox brain and RIP-Seq on Olig2cre;Prrc2aflox brain | Wu et al. [141] |
ATAC: assay for transposase-accessible chromatin, ChIP: chromatin immunoprecipitation, DamID: DNA adenine methyltransferase identification, ERRBS: enhanced reduced representation bisulfite sequencing, hMeDIP: hydroxyMethylated DNA immunoPrecipitation, RIP: RNA immunoprecipitation, RRHP: reduced representation 5-hydroxymethylcytosine profiling, rtqPCR: reverse transcription quantitative polymerase chain reaction, Seq: sequencing.