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ENL reads histone β-hydroxybutyrylation to modulate gene transcription (CUT&Tag)

ABSTRACT: Histone modifications are typically recognized by chromatin-binding protein modules (referred to as “readers”) to mediate fundamental processes such as transcription. Lysine β-hydroxybutyrylation (Kbhb) is a new type of histone mark that couples metabolism to gene expression. However, the readers that prefer histone Kbhb remain elusive. This knowledge gap must be filled in order to reveal the molecular mechanism of this epigenetic regulation. Herein, we developed a chemical proteomic approach, relying upon multivalent photoaffinity probes to capture binders of the mark and identified ENL as a novel target of H3K9bhb. Biochemical studies and CUT&Tag analysis further suggested that ENL favorably binds to H3K9bhb, and co-localizes with it on promoter regions to modulate gene expression. Notably, disrupting the interaction between H3K9bhb and ENL via structure-based mutation leads to the suppressed expression of the gene like MYC that drives cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266268 | GEO | 2024/05/06

REPOSITORIES: GEO

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ENL reads histone β-hydroxybutyrylation to modulate gene transcription (RNA-Seq)

Project description:Histone modifications are typically recognized by chromatin-binding protein modules (referred to as “readers”) to mediate fundamental processes such as transcription. Lysine β-hydroxybutyrylation (Kbhb) is a new type of histone mark that couples metabolism to gene expression. However, the readers that prefer histone Kbhb remain elusive. This knowledge gap must be filled in order to reveal the molecular mechanism of this epigenetic regulation. Herein, we developed a chemical proteomic approach, relying upon multivalent photoaffinity probes to capture binders of the mark and identified ENL as a novel target of H3K9bhb. Biochemical studies and CUT&Tag analysis further suggested that ENL favorably binds to H3K9bhb, and co-localizes with it on promoter regions to modulate gene expression. Notably, disrupting the interaction between H3K9bhb and ENL via structure-based mutation leads to the suppressed expression of the gene like MYC that drives cell proliferation.

2024-05-06 | GSE266269 | GEO

Metabolic Regulation of Gene Expression by Histone Lysine Ã-hydroxybutyrylation [RNA-seq]

Project description:We identified a new type of histone mark-lysine Ã-hydroxybutyrylation (Kbhb). This ketone body derived histone mark (Kbhb) was dramatically induced in livers during starvation. To charactize histopne Kbhb: 1) We mapped genomic distributions of histone Kbhb marks (H3K9bhb, H3K4bhb and H4K8bhb) by ChIP-seq in mouse liver. 2) We examined the response of histone Kbhb mark to starvation by carrying out ChIP-seq experiments for H3K9bhb in both "starved" and "fed" mouse liver. 3) We also examined differentially-expressed genes during starvation by carrying out RNA-seq experiments in both "starved" and "fed" mouse liver. By integrating analyses of ChIP-seq and RNA-seq data, we tried to get a correlation between H3K9bhb mark and gene expression in response to starvation. Sequencing was performed on the HiSeq2000 (Illumina). RNA-seq of mouse liver cells both in "starved" and "fed" conditions.

2016-04-06 | E-GEOD-69616 | biostudies-arrayexpress

Metabolic Regulation of Gene Expression by Histone Lysine Ã-hydroxybutyrylation [ChIP-seq]

Project description:We identified a new type of histone mark-lysine Ã-hydroxybutyrylation (Kbhb). This ketone body derived histone mark (Kbhb) was dramatically induced in livers during starvation. To charactize histopne Kbhb: 1) We mapped genomic distributions of histone Kbhb marks (H3K9bhb, H3K4bhb and H4K8bhb) by ChIP-seq in mouse liver. 2) We examined the response of histone Kbhb mark to starvation by carrying out ChIP-seq experiments for H3K9bhb in both "starved" and "fed" mouse liver. 3) We also examined differentially-expressed genes during starvation by carrying out RNA-seq experiments in both "starved" and "fed" mouse liver. By integrating analyses of ChIP-seq and RNA-seq data, we tried to get a correlation between H3K9bhb mark and gene expression in response to starvation. Sequencing was performed on the HiSeq2000 (Illumina). ChIP-seq for histone Kbhb marks in both "starved (ST)" and "fed (AL)" mouse liver cells The anti-H3K4bhb, -H3K9bhb, and -H4K8bhb antibodies were generated from PTM biolabs. The process for generating antibodies were described similarly in Cell, 2011. 146: p. 1016-1028, Mol Cell, 2015. 58(2): p. 203-15, Nat Chem Biol, 2014. 10(5): p. 365-70, except for using different immunogens.

2016-04-06 | E-GEOD-69615 | biostudies-arrayexpress

Metabolic Regulation of Gene Expression by Histone Lysine ß-hydroxybutyrylation [RNA-seq]

Project description:We identified a new type of histone mark-lysine ß-hydroxybutyrylation (Kbhb). This ketone body derived histone mark (Kbhb) was dramatically induced in livers during starvation. To charactize histopne Kbhb: 1) We mapped genomic distributions of histone Kbhb marks (H3K9bhb, H3K4bhb and H4K8bhb) by ChIP-seq in mouse liver. 2) We examined the response of histone Kbhb mark to starvation by carrying out ChIP-seq experiments for H3K9bhb in both "starved" and "fed" mouse liver. 3) We also examined differentially-expressed genes during starvation by carrying out RNA-seq experiments in both "starved" and "fed" mouse liver. By integrating analyses of ChIP-seq and RNA-seq data, we tried to get a correlation between H3K9bhb mark and gene expression in response to starvation. Sequencing was performed on the HiSeq2000 (Illumina).

2016-04-06 | GSE69616 | GEO

Metabolic Regulation of Gene Expression by Histone Lysine ß-hydroxybutyrylation [ChIP-seq]

2016-04-06 | GSE69615 | GEO

Fasting enriched metabolic enhancers associate with histone lysine 9 ß-hydroxybutyrylation

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

NAT10-mediated β-hydroxybutyrylation Rewires Genomic 3D Conformation and Replication Timing

Project description:Spatiotemporal regulation of chromatin replication (replication timing, RT） in eukaryotes is critical to maintain the genomic integrity. Here we focused on epigenetic mechanisms in rewiring genomic 3D conformation and replication timing. The results show that the novel lysine β-hydroxybutyrylation (Kbhb) modifications accelerates chromatin replication without inducing replication defects. This effect was mediated by the NAT10, a novel b-hydroxybutyryl-transferase, through regulating the association of NAT10 and CTCF with chromatin. Depletion of NAT10 and NAT10-mediated Kbhb dramatically reduce chromatin-bound NAT10 and CTCF, resulting in reorganization of genomic 3D conformation with enhanced trans- and cis-interaction in Hi-C matrix, with elevated proportion of A compartments, and with reorganized TADs boundaries. Moreover, reorganization of genomic 3D conformation contributes to rewire replication timing. These results support models in which NAT10-mediated β-hydroxybutyrylation coordinates genomic 3D conformation reorganization with replication timing alteration, and emphatically address the concept that epigenetic mechanisms reconcile genomic 3D conformation with replication timing.

2021-09-08 | GSE175731 | GEO

NAT10-mediated β-hydroxybutyrylation Rewires Genomic 3D Conformation and Replication Timing [Replication-seq]

Project description:Spatiotemporal regulation of chromatin replication (replication timing, RT) in eukaryotes is critical to maintain the genomic integrity. Here we focused on epigenetic mechanisms in rewiring genomic 3D conformation and replication timing. The results show that the novel lysine β-hydroxybutyrylation (Kbhb) modifications accelerates chromatin replication without inducing replication defects. This effect was mediated by the NAT10, a novel b-hydroxybutyryl-transferase, through regulating the association of NAT10 and CTCF with chromatin. Depletion of NAT10 and NAT10-mediated Kbhb dramatically reduce chromatin-bound NAT10 and CTCF, resulting in reorganization of genomic 3D conformation with enhanced trans- and cis-interaction in Hi-C matrix, with elevated proportion of A compartments, and with reorganized TADs boundaries. Moreover, reorganization of genomic 3D conformation contributes to rewire replication timing. These results support models in which NAT10-mediated β-hydroxybutyrylation coordinates genomic 3D conformation reorganization with replication timing alteration, and emphatically address the concept that epigenetic mechanisms reconcile genomic 3D conformation with replication timing.

2021-09-08 | GSE176359 | GEO

Mouse Cardiac Proteomics and β-hydroxybutyrylation omics Studies

Project description:β-Hydroxybutyrylation (kbhb) is a new type of post-translational modification(PTM) of lysine acylation. In recent years, kbhb modification has been shown to be involved in energy metabolism, tumor metabolism, DNA damage repair and other processes. Currently, lysine β-hydroxybutyrylation has not been studied in cardiac tissue. In this study, we performed proteomic and β-hydroxybutyrylation modification omics analysis of mouse heart tissue based on LC-MS/MS analysis. These data provide the first mammalian cardiac kbhb dataset and provide new directions for further investigation of the function of kbhb in non-histone proteins.

2023-03-14 | PXD034269 | iProX

Proteome-wide analysis and functional identification of lysine β-hydroxybutyrylation in Ustilaginoidea virens

Project description:Lysine β-hydroxybutyrylation (Kbhb) is an evolutionarily conserved and widespread post-translational modification (PTM) in active gene transcription and cellular proliferation. However, its function remains unknown in phytopathogenic fungi. Here, we report a comprehensive identification of Kbhb in the rice false smut fungus Ustilaginoidea virens. Total 2,204 Kbhb sites were identified in 852 proteins. We found that β-hydroxybutyrylated proteins were enriched in mannose type O-glycan biosynthesis, citrate cycle (TCA cycle), ribosome, glycolysis/gluconeogenesis, proteasome, glyoxylate and dicarboxylate metabolism, alanine, aspartate and glutamate metabolism, pyruvate metabolism, biosynthesis of nucleotide sugars, butanoate metabolism, arginine biosynthesis, fructose and mannose metabolism, propanoate metabolism, methane metabolism, fatty acid degradation, β-alanine metabolism, valine, leucine and isoleucine degradation, phagosome, oxidative phosphorylation pathway. This suggests Kbhb might be involved in basic life functions of Ustilaginoidea virens.

2023-10-24 | PXD039304 | Pride

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