• BMB Reports
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• 제50권11호
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• pp.537-538
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• 2017

Hypoxia affects various physiological and pathophyological processes. Hypoxia changes the expression of hypoxia-responsive genes through two main pathways. First, hypoxia activates transcription factors (TF) such as Hypoxia-inducible Factor (HIF). Second, hypoxia decreases the activity of Jumonji C domain-containing histone demethylases (JMJDs) that require $O_2$ and ${\alpha}$-Ketoglutarate (${\alpha}$-KG) as substrates. The JMJDs affect gene expression through their regulation of active or repressive histone methylations. Profiling of H3K4me3, H3K9me3, and H3K27me3 under both normoxia and hypoxia identified 75 TFs whose binding motifs were significantly enriched in the methylated regions of the genes. TFs showing similar binding strengths to their target genes might be under the 'metabolic control' which changes histone methylation and gene expression by instant changing catalytic activities of resident histone demethylases.

• Molecules and Cells
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• 제43권4호
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• pp.323-330
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• 2020

Epigenetic events like DNA methylation and histone modification can alter heritable phenotypes. Zinc is required for the activity of various epigenetic enzymes, such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone demethylases, which possess several zinc binding sites. Thus, the dysregulation of zinc homeostasis can lead to epigenetic alterations. Zinc homeostasis is regulated by Zinc Transporters (ZnTs), Zrt- and Irt-like proteins (ZIPs), and the zinc storage protein metallothionein (MT). Recent advances revealed that ZIPs modulate epigenetics. ZIP10 deficiency was found to result in reduced HATs, confirming its involvement in histone acetylation for rigid skin barrier formation. ZIP13 deficiency, which is associated with Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS), increases DNMT activity, leading to dysgenesis of dermis via improper gene expressions. However, the precise molecular mechanisms remain to be elucidated. Future molecular studies investigating the involvement of zinc and its transporters in epigenetics are warranted.

• The Plant Pathology Journal
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• 제33권2호
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• pp.193-205
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• 2017

Histone methylation plays important roles in regulating chromatin dynamics and transcription in eukaryotes. Implication of histone modifications in fungal pathogenesis is, however, beginning to emerge. Here, we report identification and functional analysis of a putative JmjC-domain-containing histone demethylase in Magnaporthe oryzae. Through bioinformatics analysis, we identified seven genes, which encode putative histone demethylases containing JmjC domain. Deletion of one gene, MoJMJ1, belonging to JARID group, resulted in defects in vegetative growth, asexual reproduction, appressorium formation as well as invasive growth in the fungus. Western blot analysis showed that global H3K4me3 level increased in the deletion mutant, compared to wild-type strain, indicating histone demethylase activity of MoJMJ1. Introduction of MoJMJ1 gene into ${\Delta}Mojmj1$ restored defects in pre-penetration developments including appressorium formation, indicating the importance of histone demethylation through MoJMJ1 during infection-specific morphogenesis. However, defects in penetration and invasive growth were not complemented. We discuss such incomplete complementation in detail here. Our work on MoJMJ1 provides insights into H3K4me3-mediated regulation of infection-specific development in the plant pathogenic fungus.

• 생명과학회지
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• 제17권3호통권83호
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• pp.444-453
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• 2007

유핵세포의 게놈(genome)은 단백-DNA복합체인 염색질(chromatin)의 형태로 존재하는데, 생명현상을 유지하기 위해서는 생명체 또는 세포가 처한 상황에 맞게 염색질의 구조를 변화시키는 역동적인 조절기전이 필요하다. 염색질을 구성하는 기본단위는 히스톤 8량체 (histone octamer)를 포함하는 뉴클레오좀(nucleosome)이다. 히스톤 단백에는 여러 종류의 공유결합성 수식이 일어나는데, 그 중 하나가 라이신 잔기(lysine residue)에 일어나는 메틸화이다. 최근 수년간의 연구로 여러 개의 히스톤 라이신 메틸화효소(histone lysine methyltransferase, HKMT), 이에 결합하는 염색질단백 및 메틸화와 관련된 후생유전학적 현상이 밝혀졌으며, 특히 정밀한 연구방법을 동원한 다방면의 실험을 통하여 비록 자세한 기전과 전체적인 윤곽의 규명은 미흡하더라도 라이신 메틸화가 후생유전학적 변화를 초래하는 일부 과정이 규명 되었다. 또한 여러 종류의 라이신 탈메틸화효소가 최근에 발견됨에 따라, 아세틸화, 인산화등 다른 공유결합성 수식보다는 상대 적으로 안정되더라도, 히스톤 메 틸화로 유발되는 후생유전학적 변화가 불가역성이 아님을 알게 되었다.

• 한국균학회소식:학술대회논문집
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• 한국균학회 2014년도 추계학술대회 및 정기총회
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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.

• BMB Reports
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• 제55권2호
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• pp.92-97
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• 2022

Lysine methylation is one of the most important histone modifications that modulate chromatin structure. In the present study, the roles of the histone lysine demethylases JMJD2a and LSD1 in CK2 downregulation-mediated senescence were investigated. The ectopic expression of JMJD2a and LSD1 suppressed the induction of senescence-associated β-galactosidase activity and heterochromatin foci formation as well as the reduction of colony-forming and cell migration ability mediated by CK2 knockdown. CK2 downregulation inhibited JMJD2a and LSD1 expression by activating the mammalian target of rapamycin (mTOR)-ribosomal p70 S6 kinase (p70S6K) pathway. In addition, the down-regulation of JMJD2a and LSD1 was involved in activating the p53-p21^Cip1/WAF1-SUV39h1-trimethylation of the histone H3 Lys9 (H3K9me3) pathway in CK2-downregulated cells. Further, CK2 downregulation-mediated JMJD2a and LSD1 reduction was found to stimulate the dimethylation of Lys370 on p53 (p53K370me2) and nuclear import of SUV39h1. Therefore, this study indicated that CK2 downregulation reduces JMJD2a and LSD1 expression by activating mTOR, resulting in H3K9me3 induction by increasing the p53K370me2-dependent nuclear import of SUV39h1. These results suggest that CK2 is a potential therapeutic target for age-related diseases.

• 한국발생생물학회지:발생과생식
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• 제15권4호
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• pp.273-279
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• 2011

후성유전학적 조절은 DNA 서열상의 변화 없이도 유전자의 기능을 변화시킬 수 있는 현상을 뜻한다. 염색체의 후성유전학적 상태는 히스톤 변형, DNA 변형 그리고 RNAi에 의한 유전자 침묵 등에 의해 조절된다. 본 총설에서는 배아줄기세포에서의 후성 유전학적 조절에 영향을 주는 요인으로서 히스톤(histone)의 메틸화에 초점을 맞추었다. 배아줄기세포에서 발현되는 유전자의 조절에는 두 가지 단백질 복합체가 관여한다. Polycomb repressive complex 2(PRC2)는 EED, EZH2, SUZ1를 주요인자로 포함하며, H3K27의 trimethylation(H3K27me3)을 증가시킴으로써 유전자의 발현을 억제한다. 이와는 대조적으로 Trithorax group(TrxG) 복합체는 주요인자로 MLL family를 포함하며, H3K4의 trimethylation(H3K4me3) 시킴으로써 유전자의 발현을 활성화한다. PRC2 및 TrxG는 다양한 보조 단백질을 포함한다. 배아줄기세포에서 후성유전학적 조절의 두드러진 특징은 H3K27me3과 H3K4me3이 동시에 나타나는 이가 상태(bivalent state)이다. PRC2와 TrxG 복합체 그리고 H3K4나 K3K27의 메틸화에 특이적으로 작용하는 탈메틸효소(demethylase)가 한데 어우러져 배아줄기세포에서 만능성 관련 유전자와 발달 관련 유전자의 발현을 조절함으로써 줄기세포의 유지 및 분화에 기여한다. 따라서 후성유전학적 조절인자들에 대한 보다 자세한 연구는 배아줄기세포를 보다 잘 이해하고 활용하는데 도움을 줄 것이다.