## 5 Epigenetic Regulation of ALS
### Studies Using Human Cell and Mouse Models
#### 5.1.3 Histone Modifications  
The histone acetyltransferase (HATs) CBP and p300 play important roles as coactivators of signal-dependent transcription factors. Pull-down assays with flag-tagged CBP and HeLa whole cell extracts identified FUS as a binding factor to CBP [68]. FUS also binds p300 and inhibits HAT activities of both CBP and p300 proteins [68]. Knockdown of _p300/CBP_ using specific small interfering RNAs (siRNANAs) reduced histone acetylation levels of lysine 9 and 14 of histone H3 (H3K9K14) in the _CyclinD1_ promoter region that was assayed by chromatin immunoprecipitation, in addition to _CyclinD1_ mRNA levels [68]. These observations suggest crucial roles of these coactivators in the activation of the _CyclinD1_ gene. Microsatellite-based genetic association studies revealed that Elongator complex protein 3 (ELP3) harboring HAT activity is associated with motor neuron degeneration in ALS [69]. ELF3 acetylates lysine 14 of histone H3 (H3K14) and lysine 8 of histone H4 (H4K8) [70]. These studies demonstrated the link between causative genes of ALS and HAT (Table 2). Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histones and other proteins. HDACs 1-11 are Zn\({}^{2+}\)-dependent HDACs, whereas Sirtuins (SIRT) 1-7 are nicotine adenine dinucleotide (NAD+)-dependent deacetylases with mono-ADP-ribosyltransferase activities [71]. HDAC1, HDAC2, HDAC3, and HDAC8 are localized in the nucleus, and exhibit ubiquitous expression in multiple organs and tissues, with relatively high expression of HDAC2 and 3 in the brain [71]. HDAC2 expression is upregulated in the motor cortex and spinal cord, particularly in the nuclei of motor neurons of ALS patients [72]. A previous study revealed that HDAC1 mis-localizes to the cytoplasm in mouse ALS models targeting _FUS_[73]. Subcellular localization of HDAC1 is regulated by phosphorylation of its serine residues and the neuroprotective function of HDAC1 accumulation in the nucleus was also reported in a mouse model [74]. HDAC6 carries two catalytic domains and functions in the cytoplasm, where HDAC6 deacetylates \(\alpha\)-tubulin to alter the stability of microtubules [75]. It was previously reported that TDP-43 and FUS interact to form a ribonucleoprotein complex that regulates the expression of HDAC6 through its mRNA stability [76]. Mutant SOD1 proteins associated with ALS are prone to aggregation. HDAC6 selectively interacted with the mutant SOD1 and knockdown of _HDAC6_ increased aggregation of the mutant SOD1 in cultured human cells (Table 2) [77]. Expression of the aggregation-prone mutant SOD1 protein increased \(\alpha\)-tubulin acetylation. Based on these observations, the mutant SOD1 associated with ALS can alter HDAC6 activity and increase \(\alpha\)-tubulin acetylation, which consequently results in facilitation of the microtubule- and retrograde transport-dependent aggregation of mutant SOD1 [77]. Among SIRT1-7, SIRT1 associates with euchromatin and can be shuttled to the cytoplasm [78]. SIRT6 preferentially localizes in heterochromatin and SIRT7 mainly localizes in the nucleolus. SIRT2 mainly localizes in the cytoplasm, playing an important role in regulating cytoskeletal dynamics. SIRT3, SIRT4, and SIRT5 localize in mitochondria [79]. In ALS model mice carrying the _SOD1_ G93A mutation, expression of both SIRT1 and SIRT2 was downregulated in neurons [80; 81]. SIRT1 deacetylates and activates Peroxisome proliferatorator-activated receptor gamma coactivator 1\(\alpha\) (PGC1-\(\alpha\)), a transcriptional coactivator involved in energy production, by stimulating mitochondrial biogenesis and the respiration rate [82]. Of note, decreases in mRNA and protein levels of PGC1-\(\alpha\) in muscle and the spinal cord were observed in both mouse models and ALS patients [83]. Thus, HDACs play important roles in the pathology of ALS (Table 2) [13; 84].