MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation

Male-specific lethal 1 (MSL1) is critical for the formation of MSL histone acetyltransferase complex which acetylates histone H4 Lys16 (H4K16ac) to activate gene expression. However, the role of MSL1 in liver regeneration is poorly understood. Here, this work identifies MSL1 as a key regulator of STAT3 and histone H4 (H4) in hepatocytes. MSL1 forms condensates with STAT3 or H4 through liquid-liquid phase separation to enrich acetyl-coenzyme A (Ac-CoA), and Ac-CoA in turn enhances MSL1 condensate formation, synergetically promoting the acetylation of STAT3 K685 and H4K16, thus stimulating liver regeneration after partial hepatectomy (PH). Additionally, increasing Ac-CoA level can enhance STAT3 and H4 acetylation, thus promoting liver regeneration in aged mice. The results demonstrate that MSL1 condensate-mediated STAT3 and H4 acetylation play an important role in liver regeneration. Thus, promoting the phase separation of MSL1 and increasing Ac-CoA level may be a novel therapeutic strategy for acute liver diseases and transplantation.