Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine

beta-hydroxybutyrate (beta-OHB) is an essential metabolic energy source during fasting and functions as a chromatin regulator by lysine beta-hydroxybutyrylation (Kbhb) modification of the core histones H3 and H4. We report that Kbhb on histone H3 (H3K9bhb) is enriched at proximal promoters of critical gene subsets associated with lipolytic and ketogenic metabolic pathways in small intestine (SI) crypts during fasting. Similar Kbhb enrichment is observed in Lgr5(+) stem cell-enriched epithelial spheroids treated with beta-OHB in vitro. Combinatorial chromatin state analysis reveals that H3K9bhb is associated with active chromatin states and that fasting enriches for an H3K9bhb-H3K27ac signature at active metabolic gene promoters and distal enhancer elements. Intestinal knockout of Hmgcs2 results in marked loss of H3K9bhb-associated loci, suggesting that local production of beta-OHB is responsible for chromatin reprogramming within the SI crypt. We conclude that modulation of H3K9bhb in SI crypts is a key gene regulatory event in response to fasting.

Automated summary

The study shows that β-OHB is an important metabolic energy source during fasting and acts as a chromatin regulator through lysine β-hydroxybutyrylation. Enrichment of H3K9bhb at critical gene promoters associated with lipolytic and ketogenic metabolic pathways in the small intestine during fasting was observed. Fasting also results in an enrichment of an H3K9bhb-H3K27ac signature at active metabolic gene promoters and distal enhancer elements.