## 6 Epigenetic Regulation of CMT
### Studies Using Human Cell and Mouse Models
#### 6.1.2 Histone Modifications  
HDAC6 functions as the major deacetylating enzyme of \(\alpha\)-tubulin and is associated with several neuropathies, including ALS, as described above [75]. Mutations in the 27-_kDa small heat-shock protein (HSPB1)_ gene can cause CMT type 2F [141]. CMT model mice carrying two different _HSPB1_ mutations (S135F and P182L) exhibited characteristics of CMT depending on the mutation [142]. It was also reported that expression of mutant HSPB1 reduced acetylated \(\alpha\)-tubulin levels and induced defects in axonal transport. Inhibition of HDAC6 increased acetylated \(\alpha\)-tubulin levels and simultaneously rescued the axonal transport defects together with the CMT-like phenotype of the model mice. Mutations in the _glycyl-tRNA synthetase_ (_GARS_) gene have been identified in CMT-type 2D patients [143]. In CMT model mice carrying C201R mutant GARS, peripheral nerves and dorsal root ganglia exhibited reduced levels of \(\alpha\)-tubulin acetylation accompanied by short neurite length and defects in mitochondrial transport [144]. Physical interaction between the glycyl-tRNA synthetase and HDAC6 was also demonstrated by co-immunoprecipitation, and this interaction was inhibited by the HDAC6 inhibitor tubastatin A [144]. The inhibition of HDAC6 also rescued defects in transport of mitochondria in neurons of the model mice. Thus, HDAC6 plays a critical role in the pathogenesis of CMT (Table 2).  
The presence of mono-ubiquitination of histone H2B at lysine 120 (H2 Bub1) located immediately downstream of the transcription initiation sites of genes may be responsible for active gene transcription by promoting di-and tri-methylation of lysine 4 and lysine 79 of histone H3, thereby increasing the processivity of RNA polymerase II with the recruitment of transcription elongation machinery [145,146]. In mice with conditional depletion of the subunit of E3 ligase responsible for mono-ubiquitination, myelination in Schwann cells abnormally produced thin unstable myelin, which resulted in a peripheral neuropathy characterized by hypomyelination and progressive degeneration of axons similar to the features of CMT [147]. H2B mono-ubiquitination induces the high expression of myelin and lipid biosynthesis genes while repressing immaturity genes. Recruitment of the E3 ligaseby Early growth response 2 (Egr2), a key transcription factor for peripheral myelination, to its target genes is also known to be required for this process (Table 2) [147].  
Mutations in the ATPase domain of Microchidia CW-type zinc finger 2 (MORC2) have recently been implicated in axonal CMT [148]. Genome-wide genetic screening identified the _MORC2_ gene as an important one for epigenetic silencing by the Human Silencing Hub (HUSH) complex. Of note, HUSH recruits MORC2 to target sites in heterochromatin [149]. Depletion of MORC2 induced chromatin decompaction at these target sites concomitant with the reduction of tri-methylation of H3K9 and transcriptional de-repression. The ATPase activity of MORC2 is required for HUSH-mediated silencing. The most common mutation found in CMT patients (R25 ZW) is in the ATPase domain, which hyper-activates HUSH-mediated silencing in neuronal cells, suggesting an underlying mechanism in the role of _MORC2_ mutations in the pathogenesis of CMT [150].