KAT7 coupled with ACSS2 boosts transcription through regulation of histone β-hydroxybutyrylation [ChIP-seq]

Histone lysine β-hydroxybutyrylation (Kbhb) links ketone metabolism to gene transcription. However, the regulatory mechanism that kenogenesis-derived β-hydroxybutyrate, present throughout cells at low concentration, orchestrates this histone mark remains largely unknown. Here, we unveil a KAT7-ACSS2 module in which ACSS2 locally generates β-hydroxybutyryl-CoA (BHB-CoA), thereby bolsters histone Kbhb through fueling KAT7. Specifically, we show that KAT7 serves as a histone β-hydroxybutyryltransferase that prefers to modulate β-hydroxybutyrylation on histone H3 lysine 9 (H3K9bhb) by utilizing ACSS2-directed BHB-CoA. Moreover, ACSS2 senses β-hydroxybutyrate and translocates into the nucleus wherein it binds to and colocalizes with KAT7 at gene promoter regions. We further show that KAT7 coupled with ACSS2 regulates specific activation of genes associated with tumor cell survival through histone Kbhb. Collectively, our findings reveal that KAT7-ACSS2 module promotes histone β-hydroxybutyrylation by providing BHB-CoA locally, highlighting the importance of linking metabolic enzyme ACSS2 and KAT7 for histone Kbhb as well as offering insight into the regulatory mechanism of cellular metabolite on epigenetic modification and gene transcription.