@article{26dfa3ae0bfa4c90b6b626714a9866ce,
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",
note = "Funding Information: The authors thank all members of the Piwnica-Worms and Rai laboratories for constructive criticism throughout the study. We also thank Erika Thompson for assistance with ultra-low mRNA sequencing, Deepavali Chakravarti for technical assistance, Karen Clise-Dwyer for flow cytometry insight, and Ming Tang for programming source codes. Mark Bedford is thanked for assistance in running histone acetylation reader arrays. Experiments performed in this study utilized the MDACC Flow Cytometry and Cellular Imaging Core Facility, funded by National Cancer Institute Cancer Center Support Grant CA016672 . Additional funding sources that supported this work include the National Cancer Institute of the National Institutes of Health under award R01CA207236 (to H.P.W.). K.R. and C.J.T. were supported by R00160578 and R01CA245395 from the NCI , RP170407 from CPRIT , a research scholar award from the American Cancer Society , and the Center for Cancer Epigenetics at MDACC . Support for M.C.B. came from T32CA186892 and F31CA210631 . Funding Information: The authors thank all members of the Piwnica-Worms and Rai laboratories for constructive criticism throughout the study. We also thank Erika Thompson for assistance with ultra-low mRNA sequencing, Deepavali Chakravarti for technical assistance, Karen Clise-Dwyer for flow cytometry insight, and Ming Tang for programming source codes. Mark Bedford is thanked for assistance in running histone acetylation reader arrays. Experiments performed in this study utilized the MDACC Flow Cytometry and Cellular Imaging Core Facility, funded by National Cancer Institute Cancer Center Support Grant CA016672. Additional funding sources that supported this work include the National Cancer Institute of the National Institutes of Health under award R01CA207236 (to H.P.W.). K.R. and C.J.T. were supported by R00160578 and R01CA245395 from the NCI, RP170407 from CPRIT, a research scholar award from the American Cancer Society, and the Center for Cancer Epigenetics at MDACC. Support for M.C.B. came from T32CA186892 and F31CA210631. Conceptualization, K.M.S. C.J.T. K.R. and H.P.-W.; methodology, C.J.T. and K.M.S.; software, C.J.T. A.R. and K.R; formal analysis, C.J.T. K.M.S. and Z.G.; investigation, C.J.T. K.M.S. P.B. M.d.l.C.B. K.L.A. E.A. S.L.J.-J. and C.W.-C.; resources, H.P.-W. and K.R.; writing – original draft, K.M.S. C.J.T. K.R. and H.P.W.; funding acquisition, K.R. and H.P.W.; coordination of study, K.R. and H.P.-W. All authors have critically read, edited, and approved the final version of the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = nov,
day = "23",
doi = "10.1016/j.celrep.2021.110044",
language = "English (US)",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}