Human physiology and pathology can be affected by different nutritional conditions. At cellular level, the availability of a nutritional component not only mediates metabolic reactions but also transmits signals for diverse biological activities. Epigenetic regulation such as DNA methylation and histone post-translational modifications is considered as one of the nutrient-mediated signaling receivers as almost all of the epigenetic enzyme activities require intermediary metabolites as cofactors. The gut microbiome as “forgotten organ” has been suggested as a metabolite generator as well as a nutrient sensor for its host organism, affecting human health and diseases. Given the metabolite-dependent activities of epigenetic regulators, the gut microbiome has a high potential to influence the epigenetics in human physiology. Here, I review the involvement of gut microbiome in diverse human diseases and the mechanisms of epigenetic regulation by different metabolites. Thereafter, I discuss how the gut microbiome-generated metabolites affect host epigenetics, raising a possibility to develop a therapeutic intervention based on the interaction between the microbiome and epigenetics for human health.
DNA Methylation ; Epigenomics* ; Gastrointestinal Microbiome* ; Histones ; Humans* ; Metabolism ; Microbiota ; Pathology ; Physiology ; Protein Processing, Post-Translational

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.
DNA Methylation/*physiology ; Epigenesis, Genetic/*physiology ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/*metabolism ; Humans ; Models, Biological ; Neoplasms/*genetics

PURPOSE: The aim of this work was to evaluate nuclear histone acetylation level and total histone acetyltransferase (HAT) and deacetylase (HDAC) activity in ejaculated sperm and their relevance to conventional sperm parameters. MATERIALS AND METHODS: Thirty-three normozoospermic men were included in this study. Semen samples were processed by swim-up and then immunostained by six acetylation antibodies (H3K9ac, H3K14ac, H4K5ac, H4K8ac, H4K12ac, and H4K16ac). Our preliminary study verified the expression of HAT/HDAC1 in mature human sperm. From vitrified-warmed sperm samples, total HAT/HDAC activity was measured by commercially available kits. Nuclear DNA integrity was also measured by TUNEL assay. RESULTS: The levels of six acetylation marks were not related with conventional sperm parameters including sperm DNA fragmentation index (DFI) as well as HAT/HDAC activity. However, sperm DFI was positively correlated with HAT activity (r=0.038 after adjustment, p<0.02). HAT activity showed a negative relationship with HDAC activity (r=-0.51, p<0.01). Strict morphology was negatively correlated with acetylation enzyme index (=HAT activity/HDAC activity) (r=-0.53, p<0.01). CONCLUSION: Our works demonstrated a significant relationship of acetylation-associated enzyme activity and strict morphology or sperm DFI.
Acetylation ; Adult ; DNA Fragmentation ; Epigenesis, Genetic ; Histone Acetyltransferases/*metabolism ; Histones/*metabolism ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Protein Processing, Post-Translational ; Semen Analysis ; Spermatozoa/*metabolism

The methylation of a 23-kDa nuclear protein increased after partial hepatectomy and methylation returned to basal levels after the initial stage of regeneration. The methylating enzyme was partially purified from rat liver by ammonium sulfate precipitation, DEAE-anion exchange chromatography and Butyl-Sepharose chromatography. The 23-kDa protein was purified from a nuclear fraction of liver tissue with SP-Sepharose. When the 23-kDa protein was methylated with the partially purified methyltransferase and analyzed on C18 high performance liquid chromatography (HPLC), the methylated acceptor amino acid was monomethyl lysine (MML). Previously, only arginine N-methylation of specific substrate proteins has been reported during liver regeneration. However, in this report, we found that lysine N-methylation increased during early hepatic regeneration, suggesting that lysine N-methylation of the 23-kDa nuclear protein may play a functional role in hepatic regeneration. The methyltransferase did not methylate other proteins such as histones, hnRNPA1, or cytochrome C, suggesting the enzyme is a 23-kDa nuclear protein- specific lysine N-methyltransferase.
Animals ; Cytochromes c/metabolism ; DNA Helicases/metabolism ; Hepatectomy ; Histone-Lysine N-Methyltransferase/*metabolism ; Histones/metabolism ; Liver ; Liver Regeneration/*physiology ; Lysine/*metabolism ; Methylation ; Proteins/*metabolism ; Rats ; Rats, Sprague-Dawley ; Research Support, Non-U.S. Gov't

Arginine methylation has been implicated in the signal transduction pathway leading to cell growth. Here we show that a regenerating rat liver following partial hepatectomy exhibited elevated methyltransferase activity as shown by increased methylation of a subset of endogenous proteins in vitro. The 20-kDa protein was shown to be a major cytosolic protein undergoing methylation in regenerating hepatocytes. Methylation of the 20-kDa protein peaked at 1 d following partial hepatectomy, which gradually declined to a basal level within the next 14 d. Likewise, methylation of exogenously added bulk histones followed the similar time kinetics as the 20-kDa protein, reflecting time-dependent changes in methyltransferase activity in regenerating hepatocytes. Presence of exogenously added bulk histone in the in vitro methylation assay resulted in dose-dependent inhibition of methylation of the 20-kDa protein. All the histone subtypes tested, histone 1, 2A, 2B, 3 or 4, were able to inhibit methylation of the 20-kDa protein while addition of cytochrome C, a-lactalbumin, carbonic anhydrase, bovine serum albumin, and g globulin minimally affected methylation of the 20-kDa protein. Since methylation of the 20-kDa protein preceded proliferation of hepatocytes upon partial hepatectomy, it is tempting to speculate that the methylated 20-kDa protein by activated histone-specific methyltransferase may be involved in an early signal critical for liver regeneration.
Animals ; Cytoplasm/*chemistry ; *Hepatectomy ; Histones/metabolism ; Humans ; Liver Regeneration/*physiology ; Methylation ; Methyltransferases/metabolism ; Protein Isoforms/metabolism ; Proteins/*metabolism ; Rats ; Rats, Sprague-Dawley ; Research Support, Non-U.S. Gov't ; Signal Transduction/physiology ; Subcellular Fractions/chemistry/metabolism

BACKGROUND/AIMS: DNA double strand break (DSB) is one of the critical types of DNA damage. When unrepaired DSB is accumulated in the nucleus of the cells having mutations in such genes as p53, it will lead to chromosomal instability and further more to mutation of tumor-activating genes resulting in tumorogenesis. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. The aim of this study was to define the differences in expression of 53BP1 and gamma-H2AX, the markers of DSB, among normal, gastric adenoma, and gastric adenocarcinoma tissues. METHODS: Tissue microarray was made with the tissues taken from 121 patients who underwent gastrectomy for gastric adenocarcinoma, and 51 patients who underwent endoscopic mucosal resection for gastric adenoma. Immunochemical stain was performed for the marker of DSB, 53BP1 and gamma-H2AX in the tissue microarray. The normal tissues were collected from histologically confirmed tissues with no cellular atypia obtained from the patients with gastric adenocarcinoma. RESULTS: In gastric carcinoma cells, 53BP1 and gamma-H2AX were highly expressed as compared to normal epithelial cells and gastric adenoma (p<0.01). There were no differences in the expression of 53BP1 and gamma-H2AX between normal epithelium and gastric adenoma. The expression of 53BP1 in the adenoma with grade II and III atypism was more elevated than in those with grade I atypism. The expression of 53BP1 and gamma-H2AX were not significantly different according to the clinicopathologic parameters in the patients with gastric adenocarcinoma. CONCLUSIONS: The DSB in DNA seems to be associated with the development of gastric adenocarcinoma, but does not affect the premalignant adenoma cells.
Adenocarcinoma/genetics/*metabolism/secondary ; Adenoma/genetics/*metabolism/pathology ; Adult ; Aged ; Aged, 80 and over ; Chromosomal Instability ; *DNA Breaks, Double-Stranded ; Female ; Histones/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Middle Aged ; Neoplasm Staging ; Stomach Neoplasms/genetics/*metabolism/pathology

PURPOSE: The purpose of the present study was to investigate the aberrance of histone H3 lysine 4 trimethylation (H3K4me3) in patients with IgA Nephropathy (IgAN). MATERIALS AND METHODS: In this study, H3K4me3 variations in peripheral blood mononuclear cells (PBMCs) from 15 IgAN patients and 15 healthy subjects were analyzed using chromatin immunoprecipitation linked to microarrays analysis (ChIP-chip). ChIP real-time PCR was used to validate the microarray results. Expression analysis by quantitative real-time PCR (qRT-PCR) revealed correlations between mRNA and H3K4me3 levels. DNA methylation status was analyzed by quantitative methylation-specific PCR. RESULTS: We found that 321 probes displayed significant H3K4me3 differences in IgAN patients compared with healthy controls. Among these probes, 154 probes displayed increased H3K4me3 and 167 probes demonstrated decreased H3K4me3. For further validation, we selected 4 key relevant genes (FCRL4, GALK2, PTPRN2 and IL1RAPL1) to study. The results of ChIP real-time PCR coincided well with the microarray data. Quantitative RT-PCR revealed the correlations between the mRNA expression and the methylation levels of H3K4me3. Different degrees of DNA methylation alterations appeared on the selected positive genes. CONCLUSION: Our studies indicated that there were significant alterations in H3K4me3 in IgAN patients. These findings may help to explain the disturbed immunity and abnormal glycosylation involved in IgAN patients.
Adult ; Case-Control Studies ; Chromatin Immunoprecipitation ; Female ; Glomerulonephritis, IGA/*genetics/*metabolism ; Histones/*metabolism ; Humans ; Leukocytes, Mononuclear/*metabolism ; Lysine/*metabolism ; Male ; Methylation ; Oligonucleotide Array Sequence Analysis/*methods ; Real-Time Polymerase Chain Reaction ; Young Adult

Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)beta, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRalpha. However, recent data suggest that GRbeta is not a dominant negative inhibitor of GRalpha in the transrepressive process and has its own functional role. We investigated the functional role of GRbeta expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-alpha-induced IL-8 release in an airway epithelial cell line. GRbeta expression was induced by treatment of epithelial cells with either dexamethasone or TNF-alpha. GRbeta was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-alpha-induced IL-8 transcription was not affected by GRbeta overexpression, rather GRbeta had its own weak suppressive activity on TNF-alpha-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRbeta overexpression, but TNF-alpha-induced histone H4 acetylation at the IL-8 promoter was decreased with GRbeta overexpression. This study suggests that GRbeta overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRbeta induces its own histone deacetylase activity around IL-8 promoter site.
Acetylation ; Cell Line, Tumor ; Dexamethasone/pharmacology ; Epithelial Cells/metabolism ; *Gene Expression Regulation ; Histones/*metabolism ; Humans ; Interleukin-8/*genetics/metabolism ; Receptors, Glucocorticoid/genetics/*metabolism ; Transcriptional Activation ; Transfection ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors/pharmacology

Silent mating type information regulation 2 homolog 1 (SIRT1) is a nicotinamide adenosine dinucleotide (NAD+)-dependent class III histone deacetylase and is distributed in central nervous system and peripheral tissue. SIRT1 interacts with various transcription factors and cofactors by histone deacetylation and is involved in the modulation of food intake, energy metabolism, circadian rhythms, learning and memory, neurogenesis and neuroprotection. Increased or decreased SIRT1 activity or levels by pharmacological treatment or in genetic animal models have demonstrated its function and role in Central Nervous System and peripheral tissue. Recent study suggests that dysregulation of SIRT1 may be involved in anxiety or depression, but relatively little is known about the involvement of SIRT1 in anxiety or depression. Therefore, through unraveling the functional role of SIRT1 in food intake, energy metabolism, learning and memory as well as neuropsychiatric disease, studies on SIRT1 can shed light on the new drug development in treating neurodegenerative disease, metabolic disorder and neuropsychiatric disorder.
Adenosine ; Anxiety ; Central Nervous System ; Circadian Rhythm ; Depression ; Eating ; Energy Metabolism ; Histone Deacetylases ; Histones ; Learning ; Light ; Memory ; Models, Animal ; Neurodegenerative Diseases ; Neurogenesis ; Niacinamide ; Sirtuin 1 ; Transcription Factors

Cancer metabolism is considered as one of major cancer hallmarks. It is important to understand cancer-specific metabolic changes and its impact on cancer biology to identify therapeutic potentials. Among cancer-specific metabolic changes, a role of serine metabolism has been discovered in various cancer types. Upregulation of serine synthesis pathway (SSP) supports cell proliferation and metastasis. The change of serine metabolism is, in part, mediated by epigenetic modifiers, such as Euchromatic histone-lysine N-methyltransferase 2 and Lysine Demethylase 4C. On the other hand, SSP also influences epigenetic landscape such as methylation status of nucleic acids and histone proteins via affecting S-adenosyl methionine production. In the review, we highlight recent evidences on interactions between SSP and epigenetic regulation in cancer. It may provide an insight on roles and regulation of SSP in cancer metabolism and the potential of serine metabolism for cancer therapy.
Biology ; Cell Proliferation ; Epigenomics* ; Hand ; Histone-Lysine N-Methyltransferase ; Histones ; Lysine ; Metabolism* ; Methionine ; Methylation ; Neoplasm Metastasis ; Nucleic Acids ; Serine* ; Up-Regulation