## 5 Epigenetic Regulation of ALS
### Studies Using Drosophila Models
#### 5.2.2 Histone Modifications  
Ethyl methanesulfonate (EMS)-based mutagenesis screening was applied to identify _Drosophila_ genes required for synaptic transmission and the development/survival of neurons. The screen identified loss-of-function mutations in the _Drosophila ELP3_ gene [69]. Similar to human ELP3, _Drosophila_ ELP3 protein exerting HAT activity is associated with the \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline \multirow{2}{*}{**Gene**} & \multirow{2}{*}{**Function**} & \multirow{2}{*}{**Transcripts**} & \multirow{2}{*}{**Alleles**} & \multicolumn{2}{c}{**Effect on**} & \multirow{2}{*}{**References**} \\  & & & & & **Human Orthologue** & & **Rough Eye and Neural** \\  & & & & & & **Phenotype** & \\ \hline \multirow{4}{*}{heat shock RNA \(\omega\) (hsr\(\omega\))} & lncRNA, nuclear speckle & & & & & [102], \\  & organization, positive & & & & & & https://flybase. \\  & regulation of apoptotic & & & & & & & org/reports/ \\  & process, protein metabolic & & & & & & FBgn001234 \\  & process & & & & & & \\ \hline \multirow{4}{*}{CR18854} & \multirow{2}{*}{lncRNA, hairpin RNA} & \multirow{2}{*}{3} & \multirow{2}{*}{5} & \multirow{2}{*}{none} & \multirow{2}{*}{suppression} & \multirow{2}{*}{[102], \\  & & & & & & & \\  & & & & & & & \\  & & & & & & & \\  & & & & & & & FBgn0285991 \\ \hline \multirow{4}{*}{CR32207} & \multirow{2}{*}{lncRNA, hairpin RNA} & \multirow{2}{*}{1} & \multirow{2}{*}{2} & \multirow{2}{*}{no effect} & \multirow{2}{*}{[102], \\  & & & & & & & \\  & & & & & & & \\  & & & & & & & \\  & & & & & & & \\ \hline \multirow{4}{*}{CR43988} & \multirow{2}{*}{lncRNA} & \multirow{2}{*}{1} & \multirow{2}{*}{1} & \multirow{2}{*}{no effect} & \multirow{2}{*}{[102], \\  & & & & & & & \\  & & & & & & & \\ \hline \multirow{4}{*}{aubergine (aub)} & binding and biogenesis of & & & & & & [110], \\  & piRNA, gamete generation, & & & & & PIWIL2, \\  & gene silencing, mRNA & & & & PIWIL3, \\  & poly(A) tail shortening & & & & & PIWIL4 \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Epigenetic regulators that affected the rough eye and/or neural phenotype induced by _caz_ knockdown. RNA polymerase II complex, and is involved in RNA processing, RNA elongation, histone acetylation, and a process related to free radical reactions. It was previously reported that ELP3 controls the expression of the gene encoding Heat shock protein 70 (HSP70) by acetylating histones H3 and H4 [111]. HSPs are well-known molecular chaperones whose expression increases in response to cellular stress. In general, motor neurons have a high threshold for activating HSPs and are therefore vulnerable to stressors such as mutant SOD1 [112]. Therefore, ELP3 was suggested to increase the expression of HSP70, thereby protecting motor neurons from degeneration. Consistent with this, intraperitoneal administration of HSP70 extended the lifespan of transgenic mice carrying the mutant _SOD1_ gene [113]. _Drosophila_ has five HDACs: Rpd3, HDAC3, HDAC4, HDAC6, and HDAC11. Rpd3 is a homologue of yeast Rpd3, and exhibits nearly equal homology to human HDAC1 and HDAC2. As described above, eye imaginal disc-specific expression of human TDP-43 induced the rough eye phenotype accompanied by retinal degeneration [93,94]. Knockdown of _Rpd3_ effectively suppressed the rough eye phenotype induced by human TDP-43 [114]. Furthermore, TDP-43 interacts with HDAC1 via its RNA-binding domains, RRM1 and RRM2, carrying the two major TDP-43 acetylation sites, lysine 142 and 192 [114]. The 2D gel-analysis of immunoprecipitated TDP-43 from cultured human cells expressing both TDP-43 and HDAC1 revealed that the acetylation level of TDP-43 was lower than that in cells expressing TDP-43 alone [114]. Thus, HDAC1 likely plays a role in TDP-43-induced toxicity by regulating the acetylation state of TDP-43. Bruchpilot (BRP) is a major component of the presynaptic density that tethers vesicles in _Drosophila_[115].