Brain histone beta-hydroxy-butyrylation couples metabolism with gene expression

The metabolic status has a well-documented influence on peripheral organs9 physiology and pathology, however mounting evidence suggests that it can also affect brain function. For example, brain resilience to aging is enhanced by caloric restriction, and ketogenic diets have been used to treat neurological diseases. Unfortunately, little is known about the impact of metabolic stimuli on brain tissue at a molecular level. Recent data obtained in liver tissue suggest that beta-hydroxybutyrate (BHB) can also be a key signaling molecule regulating gene transcription. Thus, we adopted a ketogenic metabolic challenge, based on 48 hrs of fasting, and then assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex. We found that fasting enhanced K-bhb in a variety of proteins and on histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. Since one of the most enriched functional annotations both at the epigenetic and transcriptional level was circadian rhythms, we studied the expression of core-clock genes in the cortex during fasting. We found that the diurnal oscillation of specific transcripts was modulated at distinct times of the day along the circadian cycle. Thus, our results suggest that fasting dramatically impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodelling in neural tissue cells.