• Molecules and Cells
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• 제39권11호
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• pp.783-789
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• 2016

Afflicted neurons in various neurodegenerative diseases generally display diverse and complex pathological features before catastrophic occurrence of massive neuronal loss at the late stages of the diseases. This complex nature of neuronal pathophysiology inevitably implicates systemwide changes in basic cellular activities such as transcriptional controls and signal cascades, and so on, as a cause. Recently, as one of these systemwide cellular changes associated with neurodegenerative diseases, epigenetic changes caused by protein toxicity have begun to be highlighted. Notably, recent advances in related techniques including next-generation sequencing (NGS) and mass spectrometry enable us to monitor changes in the post-translational modifications (PTMs) of histone proteins and to link these changes in histone PTMs to the specific transcriptional changes. Indeed, epigenetic alterations and consequent changes in neuronal transcriptome are now begun to be extensively studied in neurodegenerative diseases including Alzheimer's disease (AD). In this review, we will discuss details of our current understandings on epigenetic changes associated with two representative neurodegenerative diseases [AD and polyglutamine (polyQ) diseases] and further discuss possible future development of pharmaceutical treatment of the diseases through modulating these epigenetic changes.

• Genomics & Informatics
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• 제8권4호
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• pp.201-205
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• 2010

The H1 histone family, member N, testis-specific (H1FNT) is exclusively expressed in the testis, and had its possible role for sperm chromatin formation. The purpose of this study is to investigate any genetic association of H1FNT gene with male infertility, especially at the promoter region. We examined the promoter single nucleotide polymorphisms (SNP) of H1FNT gene which is located within transcription factor binding site for its association with male infertility. The statistical analysis showed that the -1129A>T polymorphism was present at a statistically significance in male infertility (p=0.0059 and 0.0349 for hetero and risk type, respectively). The dual-luciferase promoter assay was performed to examine the polymorphic effect of this promoter SNP by the cloning of promoter region (1700bp fragment) into pGL3-basic vector. In our plasmid based reporter system, there is no big difference between wild and risk type. In conclusion, H1FNT -1129A>T promoter SNP is statistically significant with male infertility, especially with subfertile (non-azoospermia) group. Further analysis of its functional polymorphic effect in vivo may provide the biological significance of testis-specific histone with spermatogenesis.

• BMB Reports
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• 제47권6호
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• pp.342-347
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• 2014

Histone acetylation/deacetylation has been known to be associated with the transcriptional regulation of various genes. The role of histone deacetylase-3 in the expression regulation of MDR1 was investigated. The expression level of HDAC3 showed an inverse relationship with the expression level of MDR1. Wild-type HDAC3, but not catalytic mutant $HDAC3^{S424A}$, negatively regulated the expression of MDR1. Wild-type HDAC3, but not catalytic mutant $HDAC3^{S424A}$, showed binding to the promoter sequences of HDAC3. HDAC3 regulated the expression level, and the binding of Ac-$H3^{K9/14}$ and Ac-$H4^{K16}$ around the MDR1 promoter sequences. The nuclear localization signal domain of HDAC3 was necessary, and sufficient for the binding of HDAC3 to the MDR1 promoter sequences and for conferring sensitivity to microtubule-targeting drugs.

• Journal of Microbiology and Biotechnology
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• 제12권2호
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• pp.286-291
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• 2002

Histone deacetylase I (HDAC1) works as one of the components in a nucleosome remodeling (NuRD) complex that consists of several proteins, including metastasis-associated protein 1 (MTA1). Since the protein-protein interaction of HDAC1 and MTA1 would appear to be important for both the integrity and functionality of the HDAC1 complex, the interruption of the HDAC1 and MTA1 interaction may be an efficient way to regulate the biological function of the HDAC1 complex. Based on this idea, a yeast two-hybrid system was constructed with HDAC1 and MTA1 expressing vectors in the DNA binding and activation domains, respectively. To verify the efficiency of the assay system, 3,500 microbial metabolite libraries were tested using the paper disc method, and KB0699 was found to inhibit the HDAC1 and MTA1 interaction without any toxicity to the wild-type yeast. Furthermore, KB0699 blocked the interaction of HDAC1 and MTA1 in an in vitro GST pull down assay and induced morphological changes in B16/BL6 melanoma cells, indicating the interruption of the HDAC1 complex function. Accordingly, these results demonstrated that the yeast assay strain developed in this study could be a valuable tool for the isolation of a HDAC1 complex disruptor.

• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.155-162
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• 2018

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant-like effects in animal models of depression. However, the molecular mechanisms underlying these behavioral actions remain unknown. Here, we demonstrate that CPP rapidly stimulates histone deacetylase (HDAC) 5 phosphorylation and nuclear export in rat hippocampal neurons. These effects are accompanied by calcium/calmodulin kinase II (CaMKII) and protein kinase D (PKD) phosphorylation. Behavioral experiments revealed that viral-mediated hippocampal knockdown of HDAC5 blocked the antidepressant effects of CPP in stressed animals. Taken together, our results imply that CPP acts via HDAC5 and suggest that HDAC5 is a common regulator contributing to the antidepressant actions of NMDA receptor antagonists such as CPP.

• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.1571-1576
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• 2016

Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy.

• BMB Reports
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• 제50권4호
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• pp.162-163
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• 2017

RNA polymerase II-interacting the Set2 methyltransferase co-transcriptionally methylates histone H3 at lysine 36 within the body of genes. This modification facilitates histone deacetylation by Rpd3S HDAC in 3' transcribed regions to suppress cryptic initiation and slow elongation. Although this pathway is important for global deacetylation, no strong effects have been seen on genome-wide transcription under optimized laboratory conditions. In contrast, this pathway slows the kinetics of mRNA induction when target genes are induced upon environmental changes. Interestingly, a majority of Set2-repressed genes are overlapped by a lncRNA transcription that targets H3K36 methylation and deacetylation by Rpd3S HDAC to mRNA promoters. Furthermore, this pathway delays the induction of many cryptic transcripts upon environmental changes. Therefore, the Set2-Rpd3S HDAC pathway functions to fine-tune expression dynamics of mRNAs and ncRNAs.

• BMB Reports
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• 제50권1호
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• pp.49-54
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• 2017

Previously, we reported that vitamin C facilitates the CpG demethylation of Foxp3 enhancer in $CD4^+Foxp3^+$ regulatory T cells (Tregs) by enhancing the activity of a DNA demethylase ten-eleven-translocation (Tet). However, it is not clear whether vitamin C affects other helper T cell lineages like T helper type 17 (Th17) cells which are related with Tregs. Here, we show that the expression of interleukin-17A (IL17) increases with the treatment of vitamin C but not with other antioxidants. Interestingly, the upregulation of IL17 was not accompanied by DNA demethylation in Il17 promoter and was independent of Tet enzymes. Rather, vitamin C reduced the trimethylation of histone H3 lysine 9 (H3K9me3) in the regulatory elements of the Il17 locus, and the effects of vitamin C were abrogated by knockdown of jumonji-C domain-containing protein 2 (jmjd2). These results suggest that vitamin C can affect the expression of IL17 by modulating the histone demethylase activity.

• 한국가축번식학회지
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• 제22권3호
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• pp.253-264
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• 1998

Porcine follicular oocyte, collected from antral follicles (2~5 mm in diameter) of gilt ovaries were matured in vitro porcine follicular fluid (pFF) with PMSG (pFF-PMSG) buffer with at 37$^{\circ}C$ under 5% CO2 in air their ability of maturation promoting factor (MPF), of GV and GVBD formation was examined followed during time after in vitro culture. Formation of second metaphase was observed in 57.6% and 71.2% of matured in with pFF-PMSG buffer to 45 and 50 hours after invitro. Porcine oocytes cultured in pFF-PMSG for various periods of up to 30 hours were stained with Hoechst-33342 and classified according to maturation before assaying. Histone H1 kinase (H1K) activity was assayed during meiotic maturation in porcine oocytes matured in pFF-PMSG buffer in vitro. In oocytes matured in pFF-PMSG, H1K activity was at the 30 hours after culture and increased about 15 fold than at the germinal vesicle stage with before at the cultured in vitro. This pattern is similar to those reported in non-mammalian species and su, pp.rts the concepts that H1K is ubiquitous in eukaryotes and controls the meiotic cell cycle in mammals. These results suggest that the maturation pFF-PMSG buffer used influences the fluctuation pattern of H1K activity and biological characteristics of porcine oocytes cultured in vitro.

• 한국식물학회:학술대회논문집
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• 한국식물학회 1996년도 제10회 식물생명공학심포지움 고등식물 발생생물학의 최근 진보
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• pp.26-38
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• 1996

To investigate the regulation of plant histone H2A gene expression, we isolated two H2A genes (TH254 and TH274) from wheat, which encode different types of variants. Both genes had an intron in the coding region. In the promoters, some characteristics sequences, such as Oct and Nona motifs, which are conserved among plant histone genes were also found, and they were located in a short region (about 120 bp) upstream from the putative TATA box. Analyses of promoter activity with H2A-GUS fusion genes in the transient system using tobacco protoplasts revealed novel types of positive cis-acting sequences in the TH254 promoter: a direct repeat of a 13-bp sequence (AGTTACATTATTG) and a stretch composed of an AT-rich sequence (ATATAGAAAATTAAAA) and a G-box (CACGTG). A quantitative S1 assay of the mRNA amounts from the TH254/GUS and TH274/GUG chimeric genes in stably transformed and cell cycle-synchronized tobacco cell lines showed that the promoters of both genes contained at least one cis-acting element responsible for S phase-specific expression. Histochemical analysis of transgenic tobacco plants carrying the chimeric genes showed that the promoters of the two H2A genes were both active in developing seedlings and flower organs but regulated in different manner.