• 한국균학회소식:학술대회논문집
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• 한국균학회 2018년도 춘계학술대회 및 임시총회
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• pp.19-19
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• 2018

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. For functional and comparative analysis of histone modifications, a web-based database (dbHiMo) was constructed first to archive and analyze histone modifying enzymes from eukaryotic species whose genome sequences are available. Based on the database entries, we carried out functional analysis of genes encoding histone modifying enzymes. 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 is 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.

• Journal of Applied Biological Chemistry
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• 제62권2호
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• pp.157-165
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• 2019

Di- and tri-methylation of lysine 4 on histone H3 (H3K4me2 and H3K4me3, respectively) are epigenetic markers of active genes. Complex associated with Set1 (COMPASS) mediates these H3K4 methylations. The involvement of COMPASS activity in secondary metabolite (SM) biosynthesis was first demonstrated with an Aspergillus nidulans cclA knockout mutant. The cclA knockout induced the transcription of two cryptic SM biosynthetic gene clusters, leading to the production of the cognate SM. Monascus spp. are filamentous fungi that have been used for food fermentation in eastern Asia, and the pigment Monascus azaphione (MAz) is their main SM. Monascus highly produces MAz, implying that the cognate biosynthetic genes are highly active in transcription. In the present study, we examined how COMPASS activity modulates MAz biosynthesis by inactivating Monascus purpureus cclA (Mp-cclA) and swd1 (Mp-swd1). For both ${\Delta}Mp-cclA$ and ${\Delta}Mp-swd1$, a reduction in MAz production, accompanied by an abated cell growth, was observed. Suppression of MAz production was more effective in an agar culture than in the submerged liquid culture. The fidelity of the ${\Delta}Mp-swd1$ phenotypes was verified by restoring the WT-like phenotypes in a reversion recombinant mutant, namely, trpCp: Mp-swd1, that was generated from the ${\Delta}Mp-swd1$ mutant. Real-time quantitative Polymerase chain reaction analysis indicated that the transcription of MAz biosynthetic genes was repressed in the ${\Delta}Mp-swd1$ mutant. This study demonstrated that MAz biosynthesis is under the control of COMPASS activity and that the extent of this regulation is dependent on growth conditions.

• Molecules and Cells
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• 제28권3호
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• pp.149-154
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• 2009

Faithful and accurate replication of the DNA molecule is essential for eukaryote organisms. Nonetheless, in the last few years it has become evident that inheritance of the chromatin states associated with different regions of the genome is as important as the faithful inheritance of the DNA sequence itself. Such chromatin states are determined by a multitude of factors that act to modify not only the DNA molecule, but also the histone proteins associated with it. For instance, histones can be posttranslationally modified, and it is well established that these posttranslational marks are involved in several essential nuclear processes such as transcription and DNA repair. However, recent evidence indicates that posttranslational modifications of histones might be relevant during DNA replication. Hence, the aim of this review is to describe the most recent publications related to the role of histone posttranslational modifications during DNA replication.

• 통합자연과학논문집
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• 제6권1호
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• pp.57-63
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• 2013

Histone deacetylase (HDACs) is an enzyme family that deacetylates histones and non-histones protein. Availability of crystal structure of HDAC8 has been a boosting factor to generate target based inhibitors. Hydroxamic class is the most studied one to generate potent inhibitors. HDAC class I and class II enzymes are emerging as a therapeutic target for cancer, diabetes, inflammation and other diseases. DNA methylation and histone modification are epigenetic mechanism, is important for the regulation of cellular functions. HDACs enzymes play essential role in gene transcription to regulate cell proliferation, migration and death. The aim of this article is to provide a comprehensive overview about structure and function of HDACs enzymes, histone deacetylase inhibitors (HDACi) and HDACs enzymes as a therapeutic target for cancer, inflammation and diabetes.

• Journal of Microbiology and Biotechnology
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• 제27권8호
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• pp.1367-1378
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• 2017

Epigenetic alterations such as DNA methylation, histone acetylation, and chromatin remodeling can control gene expression by regulating gene transcription. DNA methylation is one of the frequent epigenetic events that play important roles in cancer development. Cancer cells can gain significant resistance to anticancer drugs and escape programmed cell death through major epigenetic changes, including DNA methylation. To date, several research groups have identified instances of both (i) hypermethylation of tumor suppressor genes, and (ii) global hypomethylation of oncogenes. These changes in DNA methylation status could be used as biomarkers for the diagnosis and prognosis of cancer patients undergoing chemotherapies or other clinical therapies. Herein, we describe genes for which methylation is dependent upon anticancer drug resistance in patients with gastric cancer; we then suggest a significant epigenetic target to focus on for overcoming anticancer drug resistance.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제30권3호
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• pp.302-309
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• 2008

DNA 메틸화는 histone modification과 함께 DNA의 염기서열이 유지되면서 유전기능이 변화되고 자손까지 전달 될 수 있는 후생 유전의 중요한 한 부분이다. DNA 메틸화는 크로마틴의 구조를 변경시키는 과정을 통하여 유전자와 repetitive sequence의 표현을 억제시킬 수 있다. DNA 메틸화는 X-불활성화, 유전체 각인, 유전자 발현조절, 암 생성 등에 중요한 역할을 하는 것으로 밝혀졌고, DNA 메틸화 표지자 (DNA methylation marker)들은 종양의 진단과 치료에 대한 반응을 예측하는 지표로 활용되고 있다. 지금까지 많은 연구 성과에도 불구하고 DNA메틸화, 메틸화에 의한 gene silencing, DNA 메틸화의 표적부위 등에 대한 명확한 기전이 아직도 밝혀지지 않고 있어 향후 더 많은 기초적 연구가 필요할 것이다. 최근에는 후생 유전적 변화는 가역적이기 때문에 종양억제유전자를 억압하는 후생 유전적 변화를 제거한다면 그 종양억제유전자를 다시 활성화시킬 수 있다는 개념의 후생유전 치료법 연구로 DNA 메틸화 억제제와 histone deacetyaltion에 관여하는 HDAC의 억제제들이 항암제로서 개발되어 사용되고 있는데 향후 더 많은 약제 개발과 임상적 연구가 진행되어야 할 것이다.

• Molecules and Cells
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• 제26권1호
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• pp.93-99
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• 2008

Transcriptional silencing is regulated by promoter methylation and histone modifications such as methylation and acetylation. We constructed a Schizosaccaromyces pombe reporter strain, KCT120a, to identify modifiers of transcriptional silencing, by inserting the $ura4^+$ gene into a heterochromatic telomere region. Two compounds inhibited the activity of histone deacetylases, induced acetylation of histone H3 and caused apoptotic cell death in HeLa cells. Expression of gelsolin and $p21^{waf1/cip1}$ also increased, as it does in response to HDAC inhibitors such as TSA. Therefore, these compounds appear to be potent inhibitors of HDACs, and hence potential anti-cancer drugs. Our observations suggest that a yeast cell-based assay system for transcriptional silencing may be useful for identifying histone deacetylase inhibitors and other agents affecting chromatin remodeling.

• BMB Reports
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• 제53권2호
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• pp.112-117
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• 2020

A recent study suggested that methylation of ubiquitin-like with PHD and RING finger domain 1 (UHRF1) is regulated by SET7 and lysine-specific histone demethylase 1A (LSD1) and is essential for homologous recombination (HR). The study demonstrated that SET7-mediated methylation of UHRF1 promotes polyubiquitination of proliferating cell nuclear antigen (PCNA), inducing HR. However, studies on mediators that interact with and recruit UHRF1 to damaged lesions are needed to elucidate the mechanism of UHRF1 methylation-induced HR. Here, we identified that poly [ADP-ribose] polymerase 1 (PARP1) interacts with damage-induced methylated UHRF1 specifically and mediates UHRF1 to induce HR progression. Furthermore, cooperation of UHRF1-PARP1 is essential for cell viability, suggesting the importance of the interaction of UHRF1-PARP1 for damage tolerance in response to damage. Our data revealed that PARP1 mediates the HR mechanism, which is regulated by UHRF1 methylation. The data also indicated the significant role of PARP1 as a mediator of UHRF1 methylation-correlated HR pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제17권5호
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• pp.2499-2506
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• 2016

Background: Gastric cancer (GC) is the second leading cause of cancer-related death worldwide. Several environmental, genetic and epigenetic factors have been suggested to have a role in GC development. Epigenetic mechanisms like histone changes and promoter hyper-methylation are now being increasingly studied. Associations between methylation of many gene promoters with the risk of gastric cancer have been investigated worldwide. Such aberrant methylation may result in silencing of specific genes related to cell cycling, cell adhesion, apoptosis and DNA repair. Thus this molecular mechanism might have a key role in proliferation and migration of cancerous cells. Materials and Methods: In this review article we included studies conducted on DNA methylation and gastric cancer in Iranian populations. Using Science direct, Pubmed/PMC, Springer, Wiley online library and SciELO databases, all published data until 31 January 2016 were gathered. We also searched Science direct data base for similar investigations around the world to make a comparison between Iran and other countries. Results: By searching these databases, we found that the association between methylation of seven gene promoters and gastric cancer had been studied in Iran until 31 January 2016. These genes were p16, hLMH1, E-cadherin, CTLA4, $THR{\beta}$, mir9 and APC. Searching in science direct database also showed that 92 articles had been published around the world till January 2016. Our investigation revealed that despite the importance of GC and its high prevalence in Iran, the methylation status of only a few gene promoters has been studied so far. More studies with higher sample numbers are needed to reveal the relation of methylation status of gene promoters to gastric cancer in Iran. Conclusions: Further studies will be helpful in identifying associations of DNA methylation in candidate genes with gastric cancer risk in Iranian populations.

• Journal of Plant Biotechnology
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• 제35권2호
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• pp.133-140
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• 2008

DNA와 histone 단백질의 변형은 식물 발달에 상당히 중요한 역할을 하는 것으로 알려져 있다. 식물 조직 배양 및 식물 발달 단계에서 methylation의 영향을 알아보고자 벼 종자로부터 캘러스 형성 및 식물체 재분화 단계에서 demethylation 물질인 5-azacytidine을 처리하여 유전자 발현 양상을 분석하였다. 식물체로의 재분화 능력이 있는 벼 배상체 캘러스는 5-azaC가 첨가된 H6A 배지에서는 형성되지 않았으며 갈색을 띠는 캘러스가 형성되었다. 또한 정상적인 캘러스를 5-azaC가 첨가된 MSRA 재분화 배지에서 배양했을 때도 대조구와는 달리 식물체 재분화는 이루어지지 않았다. 이러한 결과는 5-azaC가 정상적인 배상체 캘러스 및 shoot 분화에 부정적인 영향을 미친다는 것을 나타냈으며 따라서 DNA methylation이 식물 조직배양에서의 정상적인 세포 dedifferentiation과 differentiation에 필수 요인이라는 것을 알 수 있었다. 벼 캘러스 형성 및 재분화 과정 동안의 methylation 영향을 알아보고자 각 단계별로 5-azaC를 처리 후 $GeneFishig^{TM}$ DEG와 DNA chip을 사용하여 유전자 발현 양상을 분석하였다. Epigenetic regulation, 전자전달, 핵산대사, 스트레스 반응에 관여하는 일부 유전자들의 발현이 증가하거나 감소하는 것을 알 수 있었다. 발현 차이가 있는 일부 유전자를 클로닝하여 확인하였고 RT-PCR 및 northern 분석으로 각 단계에서의 발현 차이를 할인하였다.