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

doi:10.1016/j.celrep.2021.110044

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 journal › Article › peer-review

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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 language	English (US)
Article number	110044
Journal	Cell Reports
Volume	37
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2021.110044
State	Published - Nov 23 2021

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Research Animal Support Facility
Protein Array and Analysis Core
Flow Cytometry and Cellular Imaging Facility

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10.1016/j.celrep.2021.110044

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Terranova, C. J., Stemler, K. M., Barrodia, P., Jeter-Jones, S. L., Ge, Z., de la Cruz Bonilla, M., Raman, A., Cheng, C. W., Allton, K. L., Arslan, E., Yilmaz, Ö. H., Barton, M. C., Rai, K., & Piwnica-Worms, H. (2021). Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine. Cell Reports, 37(8), Article 110044. https://doi.org/10.1016/j.celrep.2021.110044

Terranova, CJ, Stemler, KM, Barrodia, P, Jeter-Jones, SL, Ge, Z, de la Cruz Bonilla, M, Raman, A, Cheng, CW, Allton, KL, Arslan, E, Yilmaz, ÖH, Barton, MC, Rai, K & Piwnica-Worms, H 2021, 'Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine', Cell Reports, vol. 37, no. 8, 110044. https://doi.org/10.1016/j.celrep.2021.110044

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title = "Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine",

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.",

keywords = "chromatin states, fasting response, gene expression, histone modifications, ketogenic, small intestine crypts, β-hydroxybutyrate",

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

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doi = "10.1016/j.celrep.2021.110044",

language = "English (US)",

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AU - Terranova, Christopher J.

AU - Stemler, Kristina M.

AU - Barrodia, Praveen

AU - Jeter-Jones, Sabrina L.

AU - Ge, Zhongqi

AU - de la Cruz Bonilla, Marimar

AU - Raman, Ayush

AU - Cheng, Chia Wei

AU - Allton, Kendra L.

AU - Arslan, Emre

AU - Yilmaz, Ömer H.

AU - Barton, Michelle C.

AU - Rai, Kunal

AU - Piwnica-Worms, Helen

PY - 2021/11/23

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N2 - 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.

AB - 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.

KW - chromatin states

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KW - gene expression

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KW - ketogenic

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KW - β-hydroxybutyrate

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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