Brain histone beta-hydroxybutyrylation couples metabolism with gene expression

Cornuti, Sara; Chen, Siwei; Lupori, Leonardo; Finamore, Francesco; Carli, Fabrizia; Samad, Muntaha; Fenizia, Simona; Caldarelli, Matteo; Damiani, Francesca; Raimondi, Francesco; Mazziotti, Raffaele; Magnan, Christophe; Rocchiccioli, Silvia; Gastaldelli, Amalia; Baldi, Pierre; Tognini, Paola

doi:10.1007/s00018-022-04673-9

Cited by 8 publications

(9 citation statements)

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“…As seen in Table 2, despite the diverse functions of the Kbhb proteins, there is an enrichment of β-hydroxybutyrylated proteins related to the regulation of the genome and its expression, including chromatin structure, transcript processing and DNA repair (Xie et al, 2016;Huang et al, 2021;Cornuti et al, 2023) Likewise, Kbhb is enriched in proteins related to fatty acid, amino acid and pyruvate metabolism, the regulation of tricarboxylic acid cycle, oxidative phosphorylation, and detoxification pathways, among others (Koronowski et al, 2021;Hou et al, 2022;Luo et al, 2023). Interestingly, 2-day starvation induced an increase in Kbhb in the cerebral cortex, mainly in proteins involved in transcription regulation, transcription dependent on RNA pol II, and morphogenesis (Cornuti et al, 2023). Surprisingly, while approximately 53% of β-hydroxybutyrylated proteins contain only one Kbhb site, others harbor multiple or even more than ten Kbhb sites, as demonstrated in HEK293T cells treated with 10 mM BHB (Huang et al, 2021).…”

Section: Lysine β-Hydroxybutyrylation (Kbhb)mentioning

confidence: 99%

“…The rise of the physiological levels of ketone bodies whether induced by KD, starvation or the administration of BHB or its derivatives, has an impact in genome regulation and therefore in the protein content ( Xie et al, 2016 ; Cornuti et al, 2023 ).…”

Section: Ketone Bodies Induce Changes In the Proteome Patternmentioning

confidence: 99%

“…The β-hydroxybutyrylation of lysine 9 in histone 3 (H3K9bhb) is the most extensively studied Kbhb mark, known to be highly responsive to changes in BHB levels ( Terranova et al, 2021 ). It is enriched in response to high KBs levels in the liver, kidney, brain, heart and the cell lines HEK293T and MEF ( Xie et al, 2016 ; Huang et al, 2021 ; Koronowski et al, 2021 ; Hou et al, 2022 ; Cornuti et al, 2023 ; Luo et al, 2023 ). H3K9bhb has been related to the upregulation of a vast set of genes specific of each cell type or tissue.…”

Section: Ketone Bodies Induce Changes In the Proteome Patternmentioning

confidence: 99%

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The proteomic effects of ketone bodies: implications for proteostasis and brain proteinopathies

García‐Velázquez¹,

Massieu²

2023

Front. Mol. Neurosci.

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A growing body of evidence supports the beneficial effects of the ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (BHB), on diverse physiological processes and diseases. Hence, KBs have been suggested as therapeutic tools for neurodegenerative diseases. KBs are an alternative fuel during fasting and starvation as they can be converted to Ac-CoA to produce ATP. A ketogenic diet (KD), enriched in fats and low in carbohydrates, induces KB production in the liver and favors their use in the brain. BHB is the most abundant KB in the circulation; in addition to its role as energy fuel, it exerts many actions that impact the set of proteins in the cell and tissue. BHB can covalently bind to proteins in lysine residues as a new post-translational modification (PTM) named β-hydroxybutyrylation (Kbhb). Kbhb has been identified in many proteins where Kbhb sites can be critical for binding to other proteins or cofactors. Kbhb is mostly found in proteins involved in chromatin structure, DNA repair, regulation of spliceosome, transcription, and oxidative phosphorylation. Histones are the most studied family of proteins with this PTM, and H3K9bhb is the best studied histone mark. Their target genes are mainly related to cell metabolism, chromatin remodeling and the control of circadian rhythms. The role of Kbhb on physiological processes is poorly known, but it might link KB metabolism to cell signaling and genome regulation. BHB also impacts the proteome by influencing proteostasis. This KB can modulate the Unfolded Protein Response (UPR) and autophagy, two processes involved in the maintenance of protein homeostasis through the clearance of accumulated unfolded and damaged proteins. BHB can support proteostasis and regulate the UPR to promote metabolism adaptation in the liver and prevent cell damage in the brain. Also, BHB stimulates autophagy aiding to the degradation of accumulated proteins. Protein aggregation is common to proteinopathies like Alzheimer’s (AD) and Parkinson’s (PD) diseases, where the KD and BHB treatment have shown favorable effects. In the present review, the current literature supporting the effects of KBs on proteome conformation and proteostasis is discussed, as well as its possible impact on AD and PD.

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Section: Lysine β-Hydroxybutyrylation (Kbhb)mentioning

confidence: 99%

Section: Ketone Bodies Induce Changes In the Proteome Patternmentioning

confidence: 99%

Section: Ketone Bodies Induce Changes In the Proteome Patternmentioning

confidence: 99%

See 1 more Smart Citation

The proteomic effects of ketone bodies: implications for proteostasis and brain proteinopathies

García‐Velázquez¹,

Massieu²

2023

Front. Mol. Neurosci.

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“…Protein beta-hydroxybutyrylation plays important roles in various cellular processes [ 154 , 155 ]. Xie et al showed that BHB induces lysine beta-hydroxybutyrylation (Kbhb) on histones and upregulates genes involved in starvation response metabolic pathways [ 156 ].…”

Section: Molecular Mechanisms Of the Neuroprotective Effects Of Kbs A...mentioning

confidence: 99%

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

Jang,

Kim,

Lee

et al. 2023

IJMS

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Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.

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“…Among the most studied Kbhb residues is histone 3 lysine 9 (H3K9) based on its association with active gene expression when it is acetylated (H3K9ac) at promoter regions 14 . To date, several studies have used H3K9bhb chromatin immunoprecipitation (ChIP) assays to identify BHB-regulated genes in the context of BHB-treatment, starvation, or ketogenic diet 10,[15][16][17][18][19][20] ).…”

Section: Introductionmentioning

confidence: 99%

Non-specific recognition of histone modifications by H3K9bhb antibody

Tsusaka

Oses-Prieto

Lee

et al. 2023

Preprint

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Ketone bodies are short chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative source of energy for the brain, heart, and skeletal muscle. Beyond this classical metabolic role, β-hydroxybutyrate (BHB), is gaining recognition as a pleiotropic signaling molecule. Lysine β-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This novel protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments, including the mitochondria and nucleus. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against the β-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s), which are increased by deacetylation inhibition and include likely acetylations. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody.

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Brain histone beta-hydroxybutyrylation couples metabolism with gene expression

Cited by 8 publications

References 75 publications

The proteomic effects of ketone bodies: implications for proteostasis and brain proteinopathies

The proteomic effects of ketone bodies: implications for proteostasis and brain proteinopathies

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

Non-specific recognition of histone modifications by H3K9bhb antibody

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