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

Christopher J. Terranova, Kristina M. Stemler, Praveen Barrodia, Sabrina L. Jeter-Jones, Zhongqi Ge, Marimar de la Cruz Bonilla, Ayush Raman, Chia Wei Cheng, Kendra L. Allton, Emre Arslan, Ömer H. Yilmaz, Michelle C. Barton, Kunal Rai, Helen Piwnica-Worms

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

β-hydroxybutyrate (β-OHB) is an essential metabolic energy source during fasting and functions as a chromatin regulator by lysine β-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 β-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 β-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.

Original languageEnglish (US)
Article number110044
JournalCell Reports
Volume37
Issue number8
DOIs
StatePublished - Nov 23 2021
Externally publishedYes

Keywords

  • chromatin states
  • fasting response
  • gene expression
  • histone modifications
  • ketogenic
  • small intestine crypts
  • β-hydroxybutyrate

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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