## 6 Epigenetic Regulation of CMT
### Studies Using Drosophila Models  
#### 6.2.1 Noncoding RNAs  
Rough eye modifier screening using the CMT model flies targeting _dFIG4_ was carried out to identify genetic interactants with _dFIG4_. By this screen, the _CR18854_ gene encoding a lncRNA consisting of 2566 bases was identified as a gene whose depletion effectively suppressed the rough eye phenotype induced by _dFIG4_ knockdown [102]. Mutation and knockdown of _CR18854_ also suppressed the enlarged lysosome phenotype induced by Fat body-specific _dFIG4_ knockdown [102]. Of note, _CR18854_ genetically interacted with not only _dFIG4_, but also _azz_, a causative gene of ALS, whereas _hsr\(\omega\)_ lncRNA was associated with ALS but genetically interacted with _dFIG4_[102]. Both of these lncRNAs were therefore suggested to be involved in a common pathway between CMT and ALS pathogenesis [102]. More recently, another lncRNA, _CR43467_, was identified as a genetic interactant with _dFIG4_[151], whereas the depletion of other lncRNAs, such as _CR32207_ and _CR43988_, exerted no apparent effect on the phenotype induced by _dFIG4_ knockdown [102]. Knockdown of _CR43467_ rescued the aberrant morphology of synapse at the NMJ and the vacuole enlargement phenotype induced by _dFIG4_ knockdown. This lncRNA genetically interacted with other genes associated with peripheral neuropathy [151], such as _cytochrome C oxidase assembly factor 7_ (_COA7_) [152], _hydroxacycl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase beta (HADHB)_ [153], and _pyruvate dehydrogenase beta_ (_PDHB_), in _Drosophila_[154]. COA7 controls the assembly of the mitochondrial respiratory chain complexes responsible for oxidative phosphorylation and its depletion causes spinocereblar ataxia with axonal neuropathy type 3 [152]. HADHB is a subunit of the mitochondrial  
\begin{table}
\begin{tabular}{c c c c} \hline \hline  & **Epigenetic Mechanism** & **Related Epigenetic Factor** & **References** \\ \hline \multirow{8}{*}{ALS/FTD} & DNA methylation & Dnmt1, Dnmt3 & [13; 45; 46; 47; 48] \\ \cline{2-4}  & & miR-155, miR-142, miR-206, & \\  & & has-miR-46469-5p, & \\  & noncoding RNA & has-miR4299, miR-338, & \\  & & miR-638, miR-409, miR-495 & \\ \cline{2-4}  & & NEAT1, MALAT1 & [65; 66; 67] \\ \cline{2-4}  & & CBP, p300, ELP3 & [68; 70] \\ \cline{2-4}  & histone modification & HDAC1, HDAC, HDAC6, & \\  & & SIRT1, SIRT2 & [72; 73; 74; 75; 76; 77; 77; 78; 79; 80; 81; 82] \\ \cline{2-4}  & & PRMT1 & [92] \\ \hline \multirow{4}{*}{CMT} & noncoding RNA & miR-149 & [140] \\ \cline{2-4}  & histone modification & HDAC6 & [144] \\ \cline{2-4}  & & E3 ubiquitin ligase, Egr2 & [147] \\ \hline \hline \end{tabular}
\end{table}
Table 2: Summary of studies with human cells and mouse models.  
trifunctional protein (MTP) that is required for the beta-oxidation of fatty acids to produce acetyl-CoA [153]. Mutations in the _HADHB_ gene induce defects in beta-oxidation that result in MTP deficiency. MTP deficiency is associated with cardiomyopathyopathy, recurrent Leigh-like encephalopathy, the later onset of peripheral neuropathy, and myopathy with or without episodic myoglobinuria [153]. PDHB is a subunit of pyruvate dehydrogenase (PDC) that is involved in the production of acetyl-CoA [154]. Deficiency of PDC causes deficits in mitochondrial function and is associated with peripheral neuropathies [154]. The nucleotide identity between _CR43467_ and _CR18854_ was 34.9%, being relatively high, suggesting a similar cellular function for both lncRNAs [151]. Based on the nucleotide sequence homology, there may be no human homologue of _CR43467_ and _CR18854_, although it does not exclude the possibility of functional homologues. As the knockdown of _CR43467_ or _CR18854_ effectively rescued the deficits induced by the _dFIG4_ knockdown in _Drosophila_, their functional human homologues, if present, may be promising targets for CMT therapies.