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    • We notice that previous reports

    2021-09-14

    We notice that previous reports of arsenic exposure are not completely consistent with each other, in terms of exposure-changed histone acetylations. In an early investigation, As exposure (7.5 μM) of HepG2 DMPO increased H3K9ac after 24 h, when analyzed by methods of immunofluorescence and Western blot analyses. The inhibition from As was comparable to that from a potent HDAC inhibitor trichostatin A (TSA) and from a DNMT1 inhibitor 5-azacytidine. To explain such dramatic increase of H3K9ac, investigators used the colorimetric HDAC activity assay kit (Abcam, ab1432) to report that As-inhibited HDAC activity was indistinguishable from TSA-inhibited (Ramirez et al., 2008). From the same report, histone methylation marks (H3K4me2 and me3; H3K9me2 and me3; H4K20me3; H3K27me3) were not affected as measured by immunofluorescence and Western blot. Authors also concluded the induced hyperacetylation independent of any SAM depletion that might occur due to arsenic metabolism. The aforementioned H3K9 hyperacetylation, however, is in dramatic contrast to the hypoacetylation of H3K9 in As exposed mice (Cronican et al., 2013). Prenatal exposure with 100 ppb (100 μg/L) As in drinking water significantly reduced H3K9ac genomewide in cortices and hippocampi of pups. The global hypoacetylation at H3K9 in exposed mice was consistent with the reduced H3K27ac in our exposed cell lines (Fig. 3, Fig. 4, Fig. 5, Fig. 6), and reductions of both H3K9ac and H3K27ac might be explained by the p300 inhibition from our results (Fig. 2, Fig. 3). On the other hand, the discrepancy of alteration of histone acetylations in different reports might be related to cell type and dose used, as suggested by at least one initial investigation: Two human T cell lines (Jurkat and CCRF-CEM) were exposed to As at 0.1, 1, and 100 μg/L. When checked H3K9me3, its levels in two lines were not different at 0.1 μg/L and might increase at 1 μg/L (p = .19) in Jurkat (but not in CCRF-CEM) cells; when checked H3K9ac, its levels in Jurkat were increased at both 0.1 μg/L and 1 μg/L, whereas its levels in CCRF-CEM were only increased at 1 μg/L (Pournara et al., 2016). Authors also reported similar cell type-specific global decrease of H3K9me3 in sorted CD4+ T cells (but not CD8+ T cells), from individuals with increasing urinary arsenic exposure in the Argentinean Andes. When checked individuals in Bangladesh, the total urinary arsenic was inversely correlated with H3K9ac and positively with H3K9me2 in peripheral blood mononuclear cells (PBMCs) (Chervona et al., 2012b). Note that adding one methyl group to H3K9me2 becomes H3K9me3 and both are repressive marks (Dai and Wang, 2014; Wang et al., 2009a). When examined in CD4+ T cells, it seems to us that both H3K9me2 and H3K9me3 signals correlate well (Barski et al., 2007; Wang et al., 2008). Then the different trends of H3K9me3 in individuals from Argentinean Andes and H3K9ME2 in individuals from Bangladesh in association with urinary arsenic exposure are puzzling. One obvious difference between two investigations is the cell type used: the former, CD4+ T cells; the latter, PBMCs. However, the extent to which cell types may explain the different reports remains to be done. While most investigations examined histone marks on histone H3, decreased H4K16ac in response to chronic arsenic exposure in human UROtsa cells was also reported (Jo et al., 2009). This decease of H4K16ac was caused by altered expression of one of the HATs, MYST1 (also known as MOF). MOF forms two distinct multiprotein complexes (MSL and NSL) that both acetylate H4K16ac. To summarize, three independent investigations including ours showed the decreases of investigated histone acetylation marks (H3K9ac, H3K27ac, or H4K16ac) (Cronican et al., 2013; Jo et al., 2009), whereas one report showed a contradictory increase of H3K9ac (Ramirez et al., 2008). Through three biological replicates, we also demonstrated that acute As exposure decreased p300 at both mRNA and protein levels (Figs. 2C, D, 3A). Consequently, p300-specific H3K27ac was reduced as demonstrated by Western blot, ChIP-seq, and ChIP-qPCR analyses in our exposed mouse MEF cells. In our system, RNA-seq data did not show the altered expression of MYST1, different from the case in human UROtsa cells. Again, cell types and doses used may explain the different observation.