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    • BMX-IN-1 In addition to SAHA SBHA also showed

    2021-12-30

    In addition to SAHA, SBHA also showed a strong rescue effect. SAHA is a general inhibitor of HDAC function (Finnin et al., 1999, Kim and Bae, 2011), while SBHA is more specific, and has been shown to inhibit HDAC1 and HDAC3 (Richon et al., 1998). The relative level of suppression was similar in Kis knockdown animals treated with both SAHA and SBHA for bouton number, branch number, and motor behavior, which may indicate that the mechanism of suppression acts mostly through inhibition of HDAC1 and/or HDAC3 function. Further, the lack of suppression by BML-281, which is specific to HDAC6 function (Kozikowski et al., 2008), strengthens this suggestion. However, we do observe that SAHA treatment consistently shows the highest suppression across all phenotypes, even with trends towards suppression in adulthood. Therefore, we cannot rule out that inhibition of HDACs beyond HDAC1 and HDAC3 are necessary for the suppression of Kis knockdown phenotypes we observe. Further work into the genetic interactions of the individual HDACs and kismet can help elucidate this relationship. It is also possible that the antagonistic relationship between Kis and HDAC that exists during the larval stages does not persist into adulthood. Although Kis is expressed ubiquitously early in development, its expression is progressively restricted to tissues including the BMX-IN-1 and ventral nerve cord (Daubresse et al., 1999). Thus, the interaction between Kis and HDACs may be concentration dependent. In addition, chromatin remodeling proteins including CHD7 and CHD8, the mammalian orthologs of Kis, associate with other chromatin regulators in multiprotein complexes. For example, CHD7 and the chromatin remodeler PBAF physically interact in human neural crest cells (Bajpai et al., 2010). CHD8 is a component of a transcriptional complex with MAFG and the DNA methyltransferase DNMT3B in human colorectal cancer cells (Fang et al., 2014). These transcriptional complexes are remarkably diverse, using different combinations of chromatin regulators in a developmentally dependent manner (Meier and Brehm, 2014). Further experiments, possibly increasing drug dosage and/or taking a genetic approach (knocking down HDAC levels), will be required to help clarify why inhibition of HDACs differentially affects adult versus larval phenotypes. Kis has proposed roles in both general transcriptional elongation by Pol II and specific activation of target genes (Srinivasan et al., 2005, Ghosh et al., 2014, Melicharek et al., 2008, Dubruille et al., 2009, Srinivasan et al., 2008). HDACs, on the other hand, are usually associated with transcriptional repression because they lead to hypoacetylation and retention of nucleosomes (Herman et al., 2006, Bannister and Kouzarides, 2011, Grunstein, 1997). The opposing functions of these two epigenetic enzymes leads to the hypothesis that they converge on the same set of target genes to maintain a delicate balance of gene expression necessary for normal development and function (Fig. 5). It may be possible that Kis and one or more HDACs are present in the same remodeling complex, thereby mediating effects on the same set of genes. However, as there is no evidence for these proteins being present in the same complex in the literature, these two proteins may also exist in separate complexes that may have a similar set of target genes. We have shown that HDACi treatment does not significantly increase kis mRNA levels (Supplemental Fig. 4), suggesting that increased Kis levels are most likely not the cause of the antagonistic relationship observed between Kis and HDAC inhibition. More effort is necessary to improve our knowledge of this epigenetic reader and eraser crosstalk. Kis shares the most homology with CHD7, a chromatin remodeler implicated in the pathology of CHARGE syndrome (Ghosh et al., 2014, Melicharek et al., 2010, Bouazoune and Kingston, 2012). CHARGE syndrome is a congenital neurodevelopmental disorder associated with defective epigenetic regulation of gene expression during development and in adult tissues (Layman et al., 2010, Zentner et al., 2010). Currently, there are no treatments for CHARGE syndrome beyond palliative care and rehabilitation of psycho-motor function (Zentner et al., 2010, Vissers et al., 2004). Elucidation of the relationship between Kis and HDACs in our model provides insight into the genetic relationships that may be affected in CHARGE. Furthermore, the present work may identify new pharmacological targets for the treatment of CHARGE by providing rationale and guidance for the analysis of HDAC inhibition in mammalian models of CHARGE syndrome.