S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity. [Display omitted] •S6K1 directly phosphorylates histone H2B at S36 during adipogenic commitment•S6K1-mediated H2BS36 phosphorylation promotes H3K27 trimethylation by EZH2•These epigenetic changes suppress Wnt gene expression and drive adipogenesis•H2BS36p and H3K27me3 are elevated in adipose tissue from obese humans and mice Expansion of adipose mass through adipogenesis is the main cause of obesity. Yi et al. report a role for S6K1 in the transcriptional regulation of an epigenetic network mediated by histone H2B phosphorylation and histone H3 trimethylation. This results in blocking Wnt ligand production and promoting adipogenesis.