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. 2022 Mar 16;27(7):3024–3033. doi: 10.1038/s41380-022-01492-z

Fig. 2. Downregulation of Fzds in AD correlates with reduced levels of H4K16ac and the concomitant increase in Sirt2 at their promoters.

Fig. 2

A ChIP-qPCR analyses of H4K16ac at the prompters of FZD1, FZD7, FZD5 and FZD9 in Human Control and Braak I-III subjects (BI–III) showing reduced acetylation levels at FZD1 and FZD7 promoters in AD. H4K16ac levels remain unchanged at FZD5 and FZD9 promoters. B Scheme representing the epigenetic changes observed in AD, where FZD1 and FZD7 promoters present reduced levels of H4K16ac and increased levels of the histone deacetylase SIRT2. C ChIP-qPCR experiments showed reduced H4K16ac at Fzd1 and Fz7 promoters in NLGF hippocampal samples. No changes are observed for Fzd5 or Fzd9. D ChIP-qPCR analyses of Sirt2 at the prompters of Fzd1, Fzd7, Fzd5 and Fzd9 in WT and NLGF hippocampal samples showing increased Sirt2 levels at Fzd1 and Fzd7 promoters in AD. No differences are observed at Fzd5 or Fzd9 promoters. E qPCR analysis showing reduced mRNA levels of Fzd1 and Fzd7 in neuronal cultures overexpressing WT SIRT2 or NLS-SIRT2. No changes are observed for Fzd5. However, WT SIRT2 induced Fzd9 transcription. Quantification (F) and representative images (G) showing Sirt2 is found in the nucleus of postmitotic neurons. In G the first column shows merged images with DAPI (blue), GFP (green) and Sirt2 (White), second column shows GFP, third column shows Sirt2 (white) and last column shows DAPI (blue). H Quantification of cytosolic and nuclear SIRT2 and representative WB showing that 30-42% of SIRT2 is found in the nucleus in human brain. Data are represented as mean + SEM. Statistical analyses by t-Test in A for FZD1, FZD7 and by Mann-Whitney for FZD5 and FZD9; in C t-Test for Fzd1, Fzd5 and Fzd9 and by Mann-Whitney for Fzd7; in D t-Test for all genes; in E one-way ANOVA followed by Games–Howell multiple comparison for all genes. N is indicated in each bar by the number of symbols. Asterisks indicate *p < 0.05; **p < 0.01, ***p < 0.005.