Histone β-hydroxybutyrylation underlies the reno-protective effect of β-hydroxybutyrate in hypertensive Dahl Salt-Sensitive Rats [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1269477 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33745947_1.fastq.gz | Fastqsanger.gz | |||
| SRR33745947_2.fastq.gz | Fastqsanger.gz | |||
| SRR33745948_1.fastq.gz | Fastqsanger.gz | |||
| SRR33745948_2.fastq.gz | Fastqsanger.gz | |||
| SRR33745949_1.fastq.gz | Fastqsanger.gz |
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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 | GSE298451 | 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 | GSE298452 | GEO
Project description:Histone β-hydroxybutyrylation underlies the reno-protective effect of β-hydroxybutyrate in hypertensive Dahl Salt-Sensitive Rats [ATAC-seq]
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Project description:Histone lysine β-hydroxybutyrylation (Kbhb) links ketone metabolism to gene transcription. However, the regulatory mechanism that kenogenesis-derived β-hydroxybutyrate, present throughout cells at low concentration, orchestrates this histone mark remains largely unknown. Here, we unveil a KAT7-ACSS2 module in which ACSS2 locally generates β-hydroxybutyryl-CoA (BHB-CoA), thereby bolsters histone Kbhb through fueling KAT7. Specifically, we show that KAT7 serves as a histone β-hydroxybutyryltransferase that prefers to modulate β-hydroxybutyrylation on histone H3 lysine 9 (H3K9bhb) by utilizing ACSS2-directed BHB-CoA. Moreover, ACSS2 senses β-hydroxybutyrate and translocates into the nucleus wherein it binds to and colocalizes with KAT7 at gene promoter regions. We further show that KAT7 coupled with ACSS2 regulates specific activation of genes associated with tumor cell survival through histone Kbhb. Collectively, our findings reveal that KAT7-ACSS2 module promotes histone β-hydroxybutyrylation by providing BHB-CoA locally, highlighting the importance of linking metabolic enzyme ACSS2 and KAT7 for histone Kbhb as well as offering insight into the regulatory mechanism of cellular metabolite on epigenetic modification and gene transcription.
2025-07-02 | GSE267130 | GEO
Project description:Histone lysine β-hydroxybutyrylation (Kbhb) links ketone metabolism to gene transcription. However, the regulatory mechanism that kenogenesis-derived β-hydroxybutyrate, present throughout cells at low concentration, orchestrates this histone mark remains largely unknown. Here, we unveil a KAT7-ACSS2 module in which ACSS2 locally generates β-hydroxybutyryl-CoA (BHB-CoA), thereby bolsters histone Kbhb through fueling KAT7. Specifically, we show that KAT7 serves as a histone β-hydroxybutyryltransferase that prefers to modulate β-hydroxybutyrylation on histone H3 lysine 9 (H3K9bhb) by utilizing ACSS2-directed BHB-CoA. Moreover, ACSS2 senses β-hydroxybutyrate and translocates into the nucleus wherein it binds to and colocalizes with KAT7 at gene promoter regions. We further show that KAT7 coupled with ACSS2 regulates specific activation of genes associated with tumor cell survival through histone Kbhb. Collectively, our findings reveal that KAT7-ACSS2 module promotes histone β-hydroxybutyrylation by providing BHB-CoA locally, highlighting the importance of linking metabolic enzyme ACSS2 and KAT7 for histone Kbhb as well as offering insight into the regulatory mechanism of cellular metabolite on epigenetic modification and gene transcription.
2025-07-02 | GSE267129 | GEO
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.
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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: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