Restriction of Fe-S cluster biogenesis impairs PDHc and ELP3 function, resulting in decreased overall histone acetylation. (A-B) Knockdown of NFS1 (A) or PDH E2 (B) resulted in decreased histone acetylation (ac-histones) in HeLa cells. (C-D) Knockdown of NFS1 (C) or ISCU (D) reduced levels of the acetyltransferase ELP3. (E) Knockdown of FXN decreased lipoylation of PDH E2 and αKGDH E2, decreased ELP3 levels, and decreased acetylation of histones. (F) Histone acetylation decreased in RAW264.7 cells activated with LPS/IFN-γ. (G) Acetate supplementation mitigated the LPS/IFN-γ–induced decrease in histone acetylation. (H) Treatment of HeLa cells with the iron chelator deferoxamine (Dfo) decreased levels of FXN, ISCU, NFS1, ISD11, lipoyl-PDH E2, ELP3, and SDHB, decreased overall histone acetylation, and increased H3K9me3 modifications.