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

Abstract

SUMMARY 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.

Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis

“…Although the gene expression profiling in key metabolic tissues of mice and humans supports that the liver is the primary ketogenic organ with the highest Hmgcs2 expression, it is notable that the kidney, small intestine, heart, and adipose tissues showed significantly elevated Hmgcs2 expression by fasting ( Supplementary Figs. 7A and B ), consistent with previous observations [ [94] , [95] , [96] , [97] ]. As such, utilization of tissue-specific Hmgcs2 knockout and overexpression in vivo models will be required in the future to examine the functional implication of extrahepatic ketogenic effects in the development and improvement of fatty liver, respectively.…”

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

“…In tissues that synthesize ketone bodies, such as the liver and kidneys, the level of BHB increases with fasting, leading to its reaction with coenzyme A to form beta-hydroxybutyryl-CoA, which is used as a substrate for protein lysine beta-hydroxybutyrylation [ 246 ]. Protein lysine beta-hydroxybutyrylation also occurs during fasting in the small intestine [ 247 ]. The enhanced ATP levels that occur when PD neural cells oxidize ketone bodies could contribute to increased activity of the proteolytic machinery to degrade α-synuclein and misfolded proteins.…”

Role of Diet in Stem and Cancer Stem Cells

“…Histone acylation includes the addition of acyl groups derived from glycolysis (histone lactylation and succinylation), FA and protein metabolism (histone crotonylation), food additives (sodium benzoate-derived histone benzoylation), fasting-, exercise- and ketogenic diet-induced FA and ketogenic amino acid demolition (histone butyrylation and β-hydroxybutyrylation). Histone β-hydroxybutyrate (β-HB) marks active promoters of starvation-responsive genes [ 139 ] and is responsible for the protective effect on neurodegeneration, NSC maintenance [ 93 ], and small intestine crypt homeostasis [ 140 ], by inhibiting histone deacetylases (HDACs) and favoring histone and non-histone acetylation [ 93 ].…”

“…β-HB is produced in the liver in conditions of glucose depletion following starvation, carbohydrate deprivation, prolonged exercise [ 187 ] or ketogenic amino acid administration (i.e., leucine, lysine, phenylalanine, isoleucine, tryptophan, tyrosine, threonine) [ 188 ]. Besides its energetic function, β-HB has a key role in cellular signaling, modulating epigenetic modifications and gene expression [ 140 , 187 ]. In the process of β-hydroxybutyrylation, β-HB can function both as a substrate and as a cofactor, inhibiting HDAC function [ 62 ].…”

“…In the process of β-hydroxybutyrylation, β-HB can function both as a substrate and as a cofactor, inhibiting HDAC function [ 62 ]. As a result, in mouse Lgr5+ ISCs of the small intestine (SI), upon fasting, β-HB preserves acetylated lysine residues on histone and non-histone proteins and contributes to SI crypt homeostasis [ 140 ]. In the same cells, HDAC1 inhibition by ketone bodies supports the Notch pathway and improves ISC self-renewal, differentiation, and regenerative capacity [ 144 ].…”