Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice
Noncommunicable diseases (NCDs) account for over 70% of deaths worldwide.
Previous work has linked NCDs such as type 2 diabetes (T2D) to disruption of chromatin regulators. However, the exact molecular origins of these chronic conditions remain elusive.
Here, we identify the H4 lysine 16 acetyltransferase MOF as a critical regulator of central carbon metabolism.
High-throughput metabolomics unveils a systemic amino acid and carbohydrate imbalance in MOF deficient mice, manifesting in T2D predisposition.
Oral glucose tolerance testing (OGTT) reveals defects in glucose assimilation and insulin secretion in these animals.
Furthermore, Mof deficient mice are resistant to diet-induced fat gain due to defects in glucose uptake in adipose tissue. MOF-mediated H4K16ac deposition controls expression of the master regulator of glucose metabolism, Pparg and the entire downstream transcriptional network.
Glucose uptake and lipid storage can be reconstituted in MOF-depleted adipocytes in vitro by ectopic Glut4 expression, PPARγ agonist thiazolidinedione (TZD) treatment or SIRT1 inhibition.
Hence, chronic imbalance in H4K16ac promotes a destabilisation of metabolism triggering the development of a metabolic disorder, and its maintenance provides an unprecedented regulatory epigenetic mechanism controlling diet-induced obesity.
Dynamic chromatin association of IκBα is regulated by acetylation and cleavage of histone H4
IκBs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors.
Additional roles for IκB homologues have been described, including chromatin association and transcriptional regulation.
Phosphorylated and SUMOylated IκBα (pS-IκBα) binds to histones H2A and H4 in the stem cell and progenitor cell compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unknown.
Here, we show that serine 32-36 phosphorylation of IκBα favors its binding to nucleosomes and demonstrate that p-IκBα association with H4 depends on the acetylation of specific H4 lysine residues.
The N-terminal tail of H4 is removed during intestinal cell differentiation by proteolytic cleavage by trypsin or chymotrypsin at residues 17-19, which reduces p-IκBα binding.
Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-IκBα chromatin binding but, paradoxically, impaired goblet cell differentiation, comparable to IκBα deletion.
Taken together, our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-IκBα in specific stem cell compartments.
Effects of H3 and H4 histones acetylation and bindings of CREB binding protein and p300 at the promoter on hepatic expression of the gamma-glutamyltransferase gene in a streptozotocin-induced moderate hypoinsulinemic rat model
Gamma-glutamyltransferase (GGT), a marker of liver disease, has been shown to be associated with increased risk of diabetes and relative insulin secretion deficiency.
However, the mechanism of hepatic Ggt regulation has not been explored fully.
In this study, we made a concerted effort to understand the mechanism by investigating the effects of acetylation of histones H3 and H4, and bindings of histone acetyltransferases, CREB binding protein (CBP) and p300, at the Ggt promoter on the regulation of the expression Ggt gene in the livers of streptozotocin (STZ)-induced moderate hypoinsulinemia rat model.
The rats treated with STZ showed remarkably higher serum GGT level and hepatic Ggt/GGT expression than the untreated control rats.
Furthermore, the acetylation of histones H3 and H4, and the binding of CBP not p300 at the Ggt promoter regions were significantly higher in the livers of STZ rats than those of the control rats.
These results suggest that an enhanced hepatic expression of Ggt is associated with increased acetylation of histones H3 and H4 and CBP binding at the Ggt promoter in STZ-induced moderate hypoinsulinemic rats.
High-fructose diet-induced hepatic expression of the Scd1 gene is associated with increased acetylation of histones H3 and H4 and the binding of ChREBP at the Scd1 promoter in rats
Stearoyl-CoA desaturase-1 (SCD1) is a key enzyme in the biosynthesis of monounsaturated fatty acids, and the expression of the Scd1 gene is induced by the intake of the lipogenic sugar fructose.
We examined the effects of a high-fructose diet on hepatic acetylation of histones H3 and H4 and the binding of carbohydrate response element-binding protein (ChREBP) on the Scd1 gene promoter in rats. Rats were fed a control diet or a high-fructose diet for 10 days.
The intake of a high-fructose diet significantly increased histone H3 and H4 acetylation and ChREBP binding to the Scd1 gene promoter as well as the amount of triglyceride and the expression of the Scd1 gene.
These results suggest that short-term intake of high fructose upregulates expression of Scd1 by enhancing acetylation of histones H3 and H4 and binding of ChREBP at the Scd1 promoter.
Dietary supplementation with myo-inositol reduces high-fructose diet-induced hepatic ChREBP binding and acetylation of histones H3 and H4 on the Elovl6 gene in rats
ELOVL fatty acid elongase 6 (ELOVL6) is a long-chain fatty acid elongase, and the hepatic expression of the Elovl6 gene and accumulation of triglycerides (TG) are enhanced by long-term high-fructose intake.
Fatty acid synthesis genes, including Elovl6, are regulated by lipogenic transcription factors, sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP).
In addition, carbohydrate signals induce the expression of fatty acid synthase not only via these transcription factors but also via histone acetylation.
Since a major lipotrope, myo-inositol (MI), can repress short-term high-fructose-induced fatty liver and the expression of fatty acid synthesis genes, we hypothesized that MI might influence SREBP-1c, ChREBP, and histone acetylation of Elovl6 in fatty liver induced by even short-term high-fructose intake.
This study aimed to investigate whether dietary supplementation with MI affects Elovl6 expression, SREBP-1 and ChREBP binding, and acetylation of histones H3 and H4 at the Elovl6 promoter in short-term high-fructose diet-induced fatty liver in rats. Rats were fed a control diet, high-fructose diet, or high-fructose diet supplemented with 0.5% MI for 10 days.
This study showed that MI supplementation reduced short-term high-fructose diet-induced hepatic expression of the Elovl6 gene, ChREBP binding, but not SREBP-1 binding, and acetylation of histones H3 and H4 at the Elovl6 promoter.
A Purified Glucomannan Oligosaccharide from Amorphophallus konjac Improves Colonic Mucosal Barrier Function via Enhancing Butyrate Production and Histone Protein H3 and H4 Acetylation
A structurally defined konjac glucomannan oligosaccharide (KGMOS) with a relatively high molecular weight and narrow molecular weight distribution (molecular weight ranging from 3000 to 4000 Da, degree of polymerization (dp) 8-11) was prepared from native konjac glucomannan (KGM), and the beneficial effects and molecular mechanisms of KGMOS on colonic functions were investigated in C57BL/6 mice.
The results are the first to reveal that KGMOS regulated intestinal microflora composition to facilitate the production of colonic butyrate.
Histone H4 Acetylation Antibody Panel Pack |
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| C10013-1 | EpiGentek | 4 x 25 ul | 470.8 EUR |
Histone H4 Acetylation Antibody Panel Pack |
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| C10013 | EpiGentek |
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Human Histone H4 (H4) ELISA Kit |
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| DLR-H4-Hu-48T | DL Develop | 48T | 620.4 EUR |
Human Histone H4 (H4) ELISA Kit |
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| DLR-H4-Hu-96T | DL Develop | 96T | 807.6 EUR |
Mouse Histone H4 (H4) ELISA Kit |
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| DLR-H4-Mu-48T | DL Develop | 48T | 632.4 EUR |
Mouse Histone H4 (H4) ELISA Kit |
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| DLR-H4-Mu-96T | DL Develop | 96T | 825.6 EUR |
Human Histone H4 (H4) ELISA Kit |
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| RDR-H4-Hu-48Tests | Reddot Biotech | 48 Tests | 652.8 EUR |
Human Histone H4 (H4) ELISA Kit |
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| RDR-H4-Hu-96Tests | Reddot Biotech | 96 Tests | 907.2 EUR |
Mouse Histone H4 (H4) ELISA Kit |
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| RDR-H4-Mu-48Tests | Reddot Biotech | 48 Tests | 668.4 EUR |
Mouse Histone H4 (H4) ELISA Kit |
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| RDR-H4-Mu-96Tests | Reddot Biotech | 96 Tests | 928.8 EUR |
EpiQuik Global Histone H4 Acetylation Assay Kit |
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| P-4009-48 | EpiGentek | 48 Assays | 463.1 EUR |
EpiQuik Global Histone H4 Acetylation Assay Kit |
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| P-4009-96 | EpiGentek | 96 Assays | 700.7 EUR |
EpiQuik Global Histone H4 Acetylation Assay Kit |
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| P-4009 | EpiGentek |
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EpiQuik Total Histone H4 Acetylation Detection Fast Kit (Colorimetric) |
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| P-4032-48 | EpiGentek | 48 Assays | 347.6 EUR |
EpiQuik Total Histone H4 Acetylation Detection Fast Kit (Colorimetric) |
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| P-4032-96 | EpiGentek | 96 Assays | 625.9 EUR |
EpiQuik Total Histone H4 Acetylation Detection Fast Kit (Fluorometric) |
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| P-4033-48 | EpiGentek | 48 Assays | 347.6 EUR |
EpiQuik Total Histone H4 Acetylation Detection Fast Kit (Fluorometric) |
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| P-4033-96 | EpiGentek | 96 Assays | 625.9 EUR |
EpiQuik Total Histone H4 Acetylation Detection Fast Kit (Colorimetric) |
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| P-4032 | EpiGentek |
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EpiQuik Total Histone H4 Acetylation Detection Fast Kit (Fluorometric) |
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| P-4033 | EpiGentek |
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Histone H4 (H4) Protein |
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| 20-abx168034 | Abbexa |
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Histone H4 (H4) Antibody |
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| 20-abx129304 | Abbexa |
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Elevated butyrate production further increased the acetylation of histone proteins H3 and H4 and thus enhanced the transcription of the major colonic mucin gene Muc2 and the secretion of mucin elements, which represents a new molecular mechanism of KGM oligosaccharide consumption.
The findings indicate that KGM oligosaccharides with specific molecular sizes have highly desirable functional properties and potentially could improve gut health by promoting the barrier function of the colonic mucosa.