Histone β-hydroxybutyrylation underlies the reno-protective effect of β-hydroxybutyrate in hypertensive Dahl Salt-Sensitive Rats [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA1269476 | ENA |
REPOSITORIES: ENA
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Project description:Background: Previously, we demonstrated that the ketone body, β-hydroxybutyrate, is a potent antihypertensive and reno-protective metabolite in Dahl Salt-Sensitive rats. However, the mechanism by which β-hydroxybutyrate confers these beneficial effects is understudied. Here we focused on determining whether the reno-protective effect of β-hydroxybutyrate is due to its known ability to epigenetically remodel chromatin via histone β-hydroxybutyrylation. Methods: We used the same animal protocol previously used for the discovery of the renoprotective effect of β-hydroxybutyrate. Briefly, post-weaning, male and female Dahl Salt-Sensitive rats were split into two groups and supplemented with or without 1,3-Butanediol for 6 weeks. At euthanasia, circulating β-hydroxybutyrate was quantitated. Renal homogenates were examined for histone 3 lysine 9 β-hydroxybutyrylation, chromatin occupancy, transcriptomic and proteomic profiles with validations. Results: Rats supplemented with 1,3-butanediol had higher circulating β-hydroxybutyrate, renal histone β-hydroxybutyrylation and significant remodeling of chromatin. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. The most highly upregulated gene actively transcribed and translated was 3-hydroxy-3-methyglutaryl CoA Synthase 2 (Hmgcs2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures contained immune function genes, protein tyrosine phosphatase receptor type C (Ptprc) and lymphocyte cytosolic protein 1 (Lcp1), which were suppressed. Conclusions: These results reveal that renal epigenetic histone β-hydroxybutyrylation is a novel mechanism by which transcriptional regulation of both energy metabolism and immune function occur concomitantly and contribute to renoprotection in the hypertensive Dahl rat.
2025-06-06 | GSE298452 | GEO
Project description:Background: Previously, we demonstrated that the ketone body, β-hydroxybutyrate, is a potent antihypertensive and reno-protective metabolite in Dahl Salt-Sensitive rats. However, the mechanism by which β-hydroxybutyrate confers these beneficial effects is understudied. Here we focused on determining whether the reno-protective effect of β-hydroxybutyrate is due to its known ability to epigenetically remodel chromatin via histone β-hydroxybutyrylation. Methods: We used the same animal protocol previously used for the discovery of the renoprotective effect of β-hydroxybutyrate. Briefly, post-weaning, male and female Dahl Salt-Sensitive rats were split into two groups and supplemented with or without 1,3-Butanediol for 6 weeks. At euthanasia, circulating β-hydroxybutyrate was quantitated. Renal homogenates were examined for histone 3 lysine 9 β-hydroxybutyrylation, chromatin occupancy, transcriptomic and proteomic profiles with validations. Results: Rats supplemented with 1,3-butanediol had higher circulating β-hydroxybutyrate, renal histone β-hydroxybutyrylation and significant remodeling of chromatin. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. The most highly upregulated gene actively transcribed and translated was 3-hydroxy-3-methyglutaryl CoA Synthase 2 (Hmgcs2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures contained immune function genes, protein tyrosine phosphatase receptor type C (Ptprc) and lymphocyte cytosolic protein 1 (Lcp1), which were suppressed. Conclusions: These results reveal that renal epigenetic histone β-hydroxybutyrylation is a novel mechanism by which transcriptional regulation of both energy metabolism and immune function occur concomitantly and contribute to renoprotection in the hypertensive Dahl rat.
2025-06-06 | GSE298451 | GEO
Project description:Histone β-hydroxybutyrylation underlies the reno-protective effect of β-hydroxybutyrate in hypertensive Dahl Salt-Sensitive Rats [RNA-seq]
| PRJNA1269477 | ENA
Project description:Studies have shown the therapeutic effects of a ketogenic diet (KD) on epilepsy, but the effect of KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that KD significantly reduce cocaine induced-reinstatement in mice, which is accompanied by a markedly elevated level of β-hydroxybutyrate (β-OHB), the most abundant ketone body, in the hippocampus. The underlying mechanism is that β-OHB posttranslationally modify CaMKII-α with β-hydroxybutyrylation, resulting in significant inhibition of T286 autophosphorylation and downregulation of CaMKII activity. Collectively, our results reveal that β-hydroxybutyrylation is a posttranslational modification of CaMKII-α that plays a critical role in mediating the effect of KD consumption in reducing cocaine reinstatement.
2022-11-30 | PXD037321 | Pride
Project description:Lysine -hydroxybutyrylation (Kbhb) is a newly identified protein post-translational modification that derived from the ketone body β-hydroxybutyrate (BHB). BHB is synthesized in the liver from fatty acids and could be delivered to peripheral tissues when the supply of glucose is too low for the body’s energetic needs. The plasma concentration of BHB can increase up to 20 mM during starvation and in pathological conditions. Despite the progresses, how the cells that do not produce BHB respond to elevated environmental BHB remains largely unknown. Given that BHB significantly drives Kbhb, here we performed a quantitative proteomics study to characterize the BHB-induced lysine -hydroxybutyrylome and acetylome. A total of 840 unique Kbhb sites across 429 proteins were identified, with 42 sites from 39 proteins being increased by more than 50% in response to BHB. The upregulated β-hydroxybutyrylome induced by BHB are involved in aminoacyl-tRNA biosynthesis, 2-oxocarboxylic acid metabolism, citrate cycle (TCA cycle), glycolysis/gluconeogenesis, and pyruvate metabolism pathways. Moreover, some BHB-targeted Kbhb substrates are potentially linked to diseases such as cancer. Taken together, this study revealed the dynamics of lysine -hydroxybutyrylome and acetylome in response to environmental BHB, which sheds light on the roles for Khib in regulation of diverse cellular processes and provides new insights into the biological functions of BHB.
2022-04-04 | PXD029481 | Pride
Project description:The aim of this study is to assess the feasibility of beta-hydroxybutyrate (BHB) supplementation in individuals who are undergoing a standard-of-care colonoscopy or flexible sigmoidoscopy.
| 2719536 | ecrin-mdr-crc
Project description:Accurate DNA replication is essential for genome integrity, with dysregulated replication dynamics, replication stress and genomic instability-hallmarks of cancer and aging. Here, we identify NAT10-mediated β-hydroxybutyrylation (Kbhb) of histones that safeguards replication fork progression, alleviates replication stress, and preserves genomic stability. DNA fiber analyses show β-hydroxybutyrate (BHB) treatment enhances replication efficiency while maintaining fork symmetry, effects abolished by NAT10 depletion or inhibition. BrdU/EdU labeling, FACS analyses reveal that NAT10-mediated Kbhb accelerates replication fork velocity and shortens S-phase duration. LC-MS/MS profiling shows no significant changes in origin firing following BHB treatment. Mechanistically, NAT10-mediated Kbhb modulates chromatin association, thereby modulating chromatin accessibility to establish a replication-permissive environment. This epigenetic remodeling mitigates replication stress markers and genomic instability. Conserved effects in transformed and primary cell models position NAT10 as a metabolic-epigenetic nexus linking nutrient signaling to replication fidelity. Our findings suggest targeting Kbhb signaling as a potential therapeutic strategy against replication stress-associated pathologies.
2025-04-14 | GSE292952 | GEO
Project description:The experiment was carried out in triplicates in untreated, etomoxir treated and etomoxir plus beta-hydroxybutyrate (3HB) treated conditions. MES83 (Glioma-derived Mesenchymal stem cells) were either untreated or treated with 40uM of etomoxir alone or in combination with 0.5mM of beta-hydroxybutyrate for 48 hrs. The cells were collected and total RNA was extracted and the library was prepared according to the manufacturer protocol.
2020-03-31 | E-MTAB-8017 | biostudies-arrayexpress
Project description:Elucidation of metabolic flux and switch is fundamental for understanding of CD8+ memory T (Tm) cell development. Glycogen, an intracellular carbon reservoir, has long been functionally considered as the use of energy metabolism. However, our recent study indicated that glycogen metabolism, directed by a cytosolic phosphoenolpyruvate carboxykinase (Pck1), controls the formation and maintenance of CD8+ Tm cells through regulating the redox homeostasis1. This unusual metabolic program raises the question of how Pck1 is upregulated in CD8+ Tm cells. Here, we show that mitochondrial acetyl-CoA is shunted to ketogenesis, which indirectly regulates Pck1 expression. Mechanistically, ketogenesis-derived β-hydroxybutyrate (BHB) is stocked in CD8+ Tm cells, which epigenetically modifies H3K9 of FoxO1 and PGC-1α with β-hydroxybutyrylation so to upregulate these genes expression. As a result, FoxO1 and PGC-1α cooperatively upregulates Pck1 expression, thus directing the carbon flow along the gluconeogenic pathway to glycogen and the pentose phosphate pathway. These results unveil that the ketogenesis acts as an unusual metabolic pathway in CD8+ Tm cells, linking epigenetic modification required for memory development.
2019-04-13 | GSE129723 | GEO
Project description: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.
2021-11-23 | GSE122896 | GEO