Genetic and pharmaceutical manipulation of H3K9 methyltransferase Suv39h1 promotes liver regeneration by unleashing HMGB2 transcription

Abstract Robust liver regeneration counteracts and facilitates recovery from liver injuries. The underlying epigenetic mechanisms, however, are not fully understood. Here we investigated the role of suppressor of variegation 3-9 homolog 1 (Suv39h1), a histone H3K9 methyltransferase, in liver regeneration. Suv39h1 expression was repressed by DNMT1 during liver regeneration. Systemic or hepatocyte-specific deletion of Suv39h1 in mice enhanced liver regeneration and post-surgery survival following partial hepatectomy. RNA sequencing revealed high-mobility group protein B2 (HMGB2) as a target for Suv39h1. Suv39h1 downregulation in proliferating hepatocytes allowed E2F1 to activate HMGB2 transcription. Consistently, HMGB2 knockdown attenuated proliferation of hepatocytes in response to HGF treatment and suppressed liver regeneration in mice. Integrated transcriptomic analysis indicated that HMGB2 may contribute to proliferation of hepatocytes by regulating a panel of proregenerative genes. Importantly, Suv39h1 inhibition by chaetocin boosted liver regeneration in mice. Finally, a significant correlation between Suv39h1, HMGB2 and proliferative markers was identified in patients with acute liver failure. In conclusion, our data uncover an unrecognized role for Suv39h1 in liver regeneration. Therefore, targeting Suv39h1 may be considered as a viable strategy to boost liver regeneration after injury.