• Journal of Life Science
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• v.21 no.4
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• pp.616-620
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• 2011

Lysine residues of histone H3 and H4 are covalently modified in the chromatin of eukaryotic cells. Lysine 27 in histone H3 was acetylated (H3K27ac) or methylated at three levels; mono-, di-, and trimethylation (H3K27me1, H3K27me2, and H3K27me3). These modifications at H3K27 were related with gene transcription and/or chromatin structure in distinct patterns. Generally, H3K27ac and H3K27me1 were enriched in active chromatin, such as the locus control region or transcriptionally active genes, while transcriptionally inactive genes were highly marked by H3K27me2 and H3K27me3. These modifications appear to have been catalyzed by distinct histone-modifying enzymes. Recent studies suggest that the four kinds of modifications at H3K27 have inter-correlation in gene transcription or chromatin structure formation.

• 한국균학회소식:학술대회논문집
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• 2014.10a
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• pp.11-11
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• 2014

Fungal pathogens have huge impact on health and economic wellbeing of human by causing life-threatening mycoses in immune-compromised patients or by destroying crop plants. A key determinant of fungal pathogenesis is their ability to undergo developmental change in response to host or environmental factors. Genetic pathways that regulate such morphological transitions and adaptation are therefore extensively studied during the last few decades. Given that epigenetic as well as genetic components play pivotal roles in development of plants and mammals, contribution of microbial epigenetic counterparts to this morphogenetic process is intriguing yet nearly unappreciated question to date. To bridge this gap in our knowledge, we set out to investigate histone modifications among epigenetic mechanisms that possibly regulate fungal adaptation and processes involved in pathogenesis of a model plant pathogenic fungus, Magnaporthe oryzae. M. oryzae is a causal agent of rice blast disease, which destroys 10 to 30% of the rice crop annually. Since the rice is the staple food for more than half of human population, the disease is a major threat to global food security. In addition to the socioeconomic impact of the disease it causes, the fungus is genetically tractable and can undergo well-defined morphological transitions including asexual spore production and appressorium (a specialized infection structure) formation in vitro, making it a model to study fungal development and pathogenicity. For functional and comparative analysis of histone modifications, a web-based database (dbHiMo) was constructed to archive and analyze histone modifying enzymes from eukaryotic species whose genome sequences are available. Histone modifying enzymes were identified applying a search pipeline built upon profile hidden Markov model (HMM) to proteomes. The database incorporates 22,169 histone-modifying enzymes identified from 342 species including 214 fungal, 33 plants, and 77 metazoan species. The dbHiMo provides users with web-based personalized data browsing and analysis tools, supporting comparative and evolutionary genomics. Based on the database entries, functional analysis of genes encoding histone acetyltransferases and histone demethylases is under way. Here I provide examples of such analyses that show how histone acetylation and methylation is implicated in regulating important aspects of fungal pathogenesis. Current analysis of histone modifying enzymes will be followed by ChIP-Seq and RNA-seq experiments to pinpoint the genes that are controlled by particular histone modifications. We anticipate that our work will provide not only the significant advances in our understanding of epigenetic mechanisms operating in microbial eukaryotes but also basis to expand our perspective on regulation of development in fungal pathogens.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4663-4670
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• 2014

Trichostatin A (TSA) is a histone deacetylase (HDAC) inhibitor. We here investigated its effects on proliferation and apoptosis of the CNE2 carcinoma cell line, and attempted to establish genome-wide DNA methylation alteration due to differentially histone acetylation status. After cells were treated by TSA, the inhibitory rate of cell proliferation was examined with a CCK8 kit, and cell apoptosis was determined by flow cytometry. Compared to control, TSA inhibited CNE2 cell growth and induced apoptosis. Furthermore, TSA was found to induce genome-wide methylation alteration as assessed by genome-wide methylation array. Overall DNA methylation level of cells treated with TSA was higher than in controls. Function and pathway analysis revealed that many genes with methylation alteration were involved in key biological roles, such as apoptosis and cell proliferation. Three genes (DAP3, HSPB1 and CLDN) were independently confirmed by quantitative real-time PCR. Finally, we conclude that TSA inhibits CNE2 cell growth and induces apoptosis in vitro involving genome-wide DNA methylation alteration, so that it has promising application prospects in treatment of NPC in vivo. Although many unreported hypermethylated/hypomethylated genes should be further analyzed and validated, the pointers to new biomarkers and therapeutic strategies in the treatment of NPC should be stressed.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.6
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• pp.679-688
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• 2018

Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been observed in both the VPA model and ASD subjects. Although several mechanisms have been suggested, the actual mechanism underlying enhanced neurite outgrowth remains unclear. In this study, we found that VPA enhanced the expression of brain-derived neurotrophic factor (BDNF), particularly mature BDNF (mBDNF), through dual mechanisms. VPA increased the mRNA and protein expression of BDNF by suppressing the nuclear expression of methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor of BDNF. In addition, VPA promoted the expression and activity of the tissue plasminogen activator (tPA), which induces BDNF maturation through proteolytic cleavage. Trichostatin A and sodium butyrate also enhanced tPA activity, but tPA activity was not induced by valpromide, which is a VPA analog that does not induce histone acetylation, indicating that histone acetylation activity was required for tPA regulation. VPA-mediated regulation of BDNF, MeCP2, and tPA was not observed in astrocytes or neurons. Therefore, these results suggested that VPA-induced mBDNF upregulation was associated with the dysregulation of MeCP2 and tPA in developing cortical NPCs.

• Journal of Korean Neurosurgical Society
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• v.51 no.4
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• pp.191-198
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• 2012

Objective: Valproic acid (VPA), as known as histone deacetylase inhibitor, has neuroprotective effects. This study investigated the histological changes and functional recovery from spinal cord injury (SCI) associated with VPA treatment in a rat model. Methods: Locomotor function was assessed according to the Basso-Beatlie-Bresnahan scale for 2 weeks in rats after receiving twice daily intraperitoneal injections of 200 mg/kg VPA or the equivalent volume of normal saline for 7 days following SCI. The injured spinal cord was then examined histologically, including quantification of cavitation. Results: Basso-Beatlie-Bresnahan scale scores in rats receiving VPA were significantly higher than in the saline group (p<0.05). The cavity volume in the VPA group was Significantly reduced compared with the control (saline-injected) group (p<0.05). The level of histone acetylation recovered in the VPA group, while it was significantly decreased in the control rats (p<0.05). The macrophage level was significantly decreased in the VPA group (p<0.05). Conclusion: VPA influences the restoration of hyperacetylation and reduction of the inflammatory reaction resulting from SCI, and is effective for histology and motor function recovery.

• Nutrition Research and Practice
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• v.17 no.1
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• pp.13-31
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• 2023

BACKGROUND/OBJECTIVES: Epigenetic regulation by nutrients can influence the development of specific diseases. This study sought to examine the effect of individual nutrients and nutrient families in the context of preventing chronic metabolic diseases via epigenetic regulation. The inhibition of lipid accumulation and inflammation by nutrients including proteins, lipids, vitamins, and minerals were observed, and histone acetylation by histone acetyltransferase (HAT) was measured. Correlative analyses were also performed. MATERIALS/METHODS: Nutrients were selected according to information from the Korean Ministry of Food and Drug Safety. Selected nutrient functionalities, including the attenuation of fatty acid-induced lipid accumulation and lipopolysaccharide-mediated acute inflammation were evaluated in mouse macrophage Raw264.7 and mouse hepatocyte AML-12 cells. Effects of the selected nutrients on in vitro HAT inhibition were also evaluated. RESULTS: Nitric oxide (NO) production correlated with HAT activity, which was regulated by the amino acids group, suggesting that amino acids potentially contribute to the attenuation of NO production via the inhibition of HAT activity. Unsaturated fatty acids tended to attenuate inflammation by inhibiting NO production, which may be attributable to the inhibition of in vitro HAT activity. In contrast to water-soluble vitamins, the lipid-soluble vitamins significantly decreased NO production. Water- and lipid-soluble vitamins both exhibited significant inhibitory activities against HAT. In addition, calcium and manganese significantly inhibited lipid accumulation, NO production, and HAT activity. CONCLUSIONS: Several candidate nutrients and their family members may have roles in the prevention of diseases, including hepatic steatosis and inflammation-related diseases (i.e., nonalcoholic steatohepatitis) via epigenetic regulation. Further studies are warranted to determine which specific amino acids, unsaturated fatty acids and lipid-soluble vitamins or specific minerals influence the development of steatosis and inflammatory-related diseases.

• BMB Reports
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• v.56 no.3
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• pp.178-183
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• 2023

Huntington's disease (HD) is a neurodegenerative disorder, of which pathogenesis is caused by a polyglutamine expansion in the amino-terminus of huntingtin gene that resulted in the aggregation of mutant HTT proteins. HD is characterized by progressive motor dysfunction, cognitive impairment and neuropsychiatric disturbances. Histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase, has been shown to induce transport- and release-defect phenotypes in HD models, whilst treatment with HDAC6 inhibitors ameliorates the phenotypic effects of HD by increasing the levels of α-tubulin acetylation, as well as decreasing the accumulation of mutant huntingtin (mHTT) aggregates, suggesting HDAC6 inhibitor as a HD therapeutics. In this study, we employed in vitro neural stem cell (NSC) model and in vivo YAC128 transgenic (TG) mouse model of HD to test the effect of a novel HDAC6 selective inhibitor, CKD-504, developed by Chong Kun Dang (CKD Pharmaceutical Corp., Korea). We found that treatment of CKD-504 increased tubulin acetylation, microtubule stabilization, axonal transport, and the decrease of mutant huntingtin protein in vitro. From in vivo study, we observed CKD-504 improved the pathology of Huntington's disease: alleviated behavioral deficits, increased axonal transport and number of neurons, restored synaptic function in corticostriatal (CS) circuit, reduced mHTT accumulation, inflammation and tau hyperphosphorylation in YAC128 TG mouse model. These novel results highlight CKD-504 as a potential therapeutic strategy in HD.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3605-3610
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• 2016

Background: Histone acetylation in chromatin structures plays a key role in regulation of gene transcription and is strictly controlled by histone acetyltransferase (HAT) and deacetylase (HDAC) activities. HDAC deregulation has been reported in several cancers. Materials and Methods: The expression of 10 HDACs (including HDAC class I and II) was studied by quantitative reverse transcription-PCR (qRT-PCR) in a cohort of mesenchymal stem cells (MM-MSCs) from 10 multiple myeloma patients with a median age 60y. The results were compared with those obtained for normal donors. Then, a coculture system was performed between MM-MSCs and u266 cell line, in the presence or absence of sodium butyrate (NaBT), to understand the effects of HDAC inhibitors (HDACi) in MM-MSCs on multiple myeloma cases. Also, the interleukin-6 (IL-6) and vascular endothelial growth factor (VEGFA) gene expression level and apoptotic effects were investigated in MM-MSCs patients and control group following NaBT treatment. Results: The results indicated that upregulated (HDACs) and downregulated (IL6 and VEGFA) genes were differentially expressed in the MM-MSCs derived from patients with multiple myeloma and ND-MSCs from normal donors. Comparison of the MM-MSCs and ND-MSCs also showed distinct HDACs expression patterns. For the first time to our knowledge, a significant increase of apoptosis was observed in coculture with MM-MSCs treated with NaBT. Conclusions: The obtained findings elucidate a complex set of actions in MSCs in response to HDAC inhibitors, which may be responsible for anticancer effects. Also, the data support the idea that MSCs are new therapeutic targets as a potential effective strategy for MM.

• Biomolecules & Therapeutics
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• v.27 no.5
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• pp.423-434
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• 2019

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the growth and survival of cancer cells. HSP90 inhibitors mainly bind to the ATP binding site of HSP90 and inhibit HSP90 activity, and these inhibitors can be distinguished as ansamycin and non-ansamycin depending on the structure. In addition, the histone deacetylase inhibitors inhibit the activity of HSP90 through acetylation of HSP90. These HSP90 inhibitors have undergone or are undergoing clinical trials for the treatment of cancer. On the other hand, recent studies have reported that various reagents induce cleavage of HSP90, resulting in reduced HSP90 client proteins and growth suppression in cancer cells. Cleavage of HSP90 can be divided into enzymatic cleavage and non-enzymatic cleavage. Therefore, reagents inducing cleavage of HSP90 can be classified as another class of HSP90 inhibitors. We discuss that the cleavage of HSP90 can be another mechanism in the cancer treatment by HSP90 inhibition.

• Molecules and Cells
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• v.27 no.4
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• pp.481-490
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• 2009

Diverse posttranslational modifications of histones, such as acetylation and methylation, play important roles in controlling gene expression. Histone methylation in particular is involved in a broad range of biological processes, including heterochromatin formation, X-chromosome inactivation, genomic imprinting, and transcriptional regulation. Recently, it has been demonstrated that proteins containing the Jumonji (Jmj) C domain can demethylate histones. In Arabidopsis, twenty-one genes encode JmjC domain-containing proteins, which can be clustered into five clades. To address the biological roles of the Arabidopsis genes encoding JmjC-domain proteins, we analyzed the temporal and spatial expression patterns of nine genes. RT-PCR analyses indicate all nine Arabidopsis thaliana Jmj (AtJmj) genes studied are actively expressed in various tissues. Furthermore, studies of transgenic plants harboring AtJmj::${\beta}$-glucuronidase fusion constructs reveal that these nine AtJmj genes are expressed in a developmentally and spatially regulated manner.