Epigenetic control of abiotic stress signaling in plants

Chung Sunglan,Kwon Chian,Lee Jae-Hoon 한국유전학회 2022 Genes & Genomics Vol.44 No.3

Background: Although plants may be regularly exposed to various abiotic stresses, including drought, salt, cold, heat, heavy metals, and UV-B throughout their lives, it is not possible to actively escape from such stresses due to the immobile nature of plants. To overcome adverse environmental stresses, plants have developed adaptive systems that allow appropriate responses to diverse environmental cues; such responses can be achieved by fine-tuning or controlling genetic and epigenetic regulatory systems. Epigenetic mechanisms such as DNA or histone modifications and modulation of chromatin accessibility have been shown to regulate the expression of stress-responsive genes in struggles against abiotic stresses. Objective: Herein, the current progress in elucidating the epigenetic regulation of abiotic stress signaling in plants has been summarized in order to further understand the systems plants utilize to effectively respond to abiotic stresses. Methods: This review focuses on the action mechanisms of various components that epigenetically regulate plant abiotic stress responses, mainly in terms of DNA methylation, histone methylation/acetylation, and chromatin remodeling. Conclusions: This review can be considered a basis for further research into understanding the epigenetic control system for abiotic stress responses in plants. Moreover, the knowledge of such systems can be effectively applied in developing novel methods to generate abiotic stress resistant crops.

Roles of ErbB3-binding protein 1 (EBP1) in embryonic development and gene-silencing control

Ko, Hyo Rim,Hwang, Inwoo,Jin, Eun-Ju,Yun, Taegwan,Ryu, Dongryeol,Kang, Jong-Sun,Park, Kye Won,Shin, Joo-Ho,Cho, Sung-Woo,Lee, Kyung-Hoon,Ye, Keqiang,Ahn, Jee-Yin National Academy of Sciences 2019 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.116 No.49

<P><B>Significance</B></P><P><I>Ebp1</I> deletion causes developmental defects with massive cell death and cessation of cell proliferation through dysregulation of epigenetic gene silencing unit, a Suv39H1/DNMT1 axis. Our study indicates that EBP1 regulates global gene expression via at least 2 mechnaisms. First, EBP1 acts as a transcriptional repressor for DNMT1 gene expression, allowing the escape of the repressive chromatin state. Second, EBP1 binds to the promoter region of the target gene inhibiting the association of DNMT1 with the downstream gene such as <I>Survivin</I>, regulating gene expression. Hence, these findings provide a molecular mechanism of how EBP1 functions in cell survival and transcriptional regulation by modulating epigenetic regulators during development.</P><P>ErbB3-binding protein 1 (EBP1) is implicated in diverse cellular functions, including apoptosis, cell proliferation, and differentiation. Here, by generating genetic inactivation of <I>Ebp1</I> mice, we identified the physiological roles of EBP1 in vivo. Loss of <I>Ebp1</I> in mice caused aberrant organogenesis, including brain malformation, and death between E13.5 and 15.5 owing to severe hemorrhages, with massive apoptosis and cessation of cell proliferation. Specific ablation of Ebp1 in neurons caused structural abnormalities of brain with neuron loss in [Nestin-Cre; <I>Ebp1</I><SUP><I>flox/flox</I></SUP>] mice. Notably, global methylation increased with high levels of the gene-silencing unit Suv39H1/DNMT1 in <I>Ebp1</I>-deficient mice. EBP1 repressed the transcription of <I>Dnmt1</I> by binding to its promoter region and interrupted DNMT1-mediated methylation at its target gene, <I>Survivin</I> promoter region. Reinstatement of EBP1 into embryo brain relived gene repression and rescued neuron death. Our findings uncover an essential role for EBP1 in embryonic development and implicate its function in transcriptional regulation.</P>

The Histone Demethylase PHF2 Promotes Fat Cell Differentiation as an Epigenetic Activator of Both C/EBPα and C/EBPδ

Lee, Kyoung-Hwa,Ju, Uk-Il,Song, Jung-Yup,Chun, Yang-Sook Korean Society for Molecular and Cellular Biology 2014 Molecules and cells Vol.37 No.10

Histone modifications on major transcription factor target genes are one of the major regulatory mechanisms controlling adipogenesis. Plant homeodomain finger 2 (PHF2) is a Jumonji domain-containing protein and is known to demethylate the histone H3K9, a repressive gene marker. To better understand the function of PHF2 in adipocyte differentiation, we constructed stable PHF2 knock-down cells by using the mouse pre-adipocyte cell line 3T3-L1. When induced with adipogenic media, PHF2 knock-down cells showed reduced lipid accumulation compared to control cells. Differential expression using a cDNA microarray revealed significant reduction of metabolic pathway genes in the PHF2 knock-down cell line after differentiation. The reduced expression of major transcription factors and adipokines was confirmed with reverse transcription- quantitative polymerase chain reaction and Western blotting. We further performed co-immunoprecipitation analysis of PHF2 with four major adipogenic transcription factors, and we found that CCATT/enhancer binding protein (C/EBP)${\alpha}$ and C/EBP${\delta}$ physically interact with PHF2. In addition, PHF2 binding to target gene promoters was confirmed with a chromatin immunoprecipitation experiment. Finally, histone H3K9 methylation markers on the PHF2-binding sequences were increased in PHF2 knock-down cells after differentiation. Together, these results demonstrate that PHF2 histone demethylase controls adipogenic gene expression during differentiation.

The Histone Demethylase PHF2 Promotes Fat Cell Differentiation as an Epigenetic Activator of Both C/EBPα and C/EBPδ

이경화,주욱일,송정엽,전양숙 한국분자세포생물학회 2014 Molecules and cells Vol.37 No.10

Histone modifications on major transcription factor target genes are one of the major regulatory mechanisms controlling adipogenesis. Plant homeodomain finger 2 (PHF2) is a Jumonji domain-containing protein and is known to demethylate the histone H3K9, a repressive gene marker. To better understand the function of PHF2 in adipocyte differentiation, we constructed stable PHF2 knock-down cells by using the mouse pre-adipocyte cell line 3T3-L1. When induced with adipogenic media, PHF2 knock-down cells showed reduced lipid accumulation compared to control cells. Differential expression using a cDNA microarray revealed significant reduction of metabolic pathway genes in the PHF2 knock-down cell line after differentiation. The reduced expression of major transcription factors and adipokines was confirmed with reverse transcription- quantitative polymerase chain reaction and Western blotting. We further performed co-immunoprecipitation analysis of PHF2 with four major adipogenic transcription factors, and we found that CCATT/enhancer binding protein (C/EBP) and C/EBP physically interact with PHF2. In addition, PHF2 binding to target gene promoters was confirmed with a chromatin immunoprecipitation experiment. Finally, histone H3K9 methylation markers on the PHF2-binding sequences were increased in PHF2 knock-down cells after differentiation. Together, these results demonstrate that PHF2 histone demethylase controls adipogenic gene expression during differentiation.

Tumor‐mediated down‐regulation of MHC class II in DC development is attributable to the epigenetic control of the CIITA type I promoter

Choi, Young‐,Eun,Yu, Ha‐,Nul,Yoon, Cheol‐,Hee,Bae, Yong‐,Soo WILEY‐VCH Verlag 2009 European journal of immunology Vol.39 No.3

<P><B>Abstract</B></P><P>In patients with cancer, DC express significantly lower amounts of MHC class II compared with those of normal individuals. However, the underlying mechanisms for this have not yet been fully defined. In the present study, we found that IL‐10 plays a major role in the tumor‐conditioned medium (TCM)‐mediated decrease of MHC class II expression on BM‐derived DC. IL‐10 inhibited the expression of type I CIITA during DC differentiation. GM‐CSF‐mediated histone (H3 and H4) acetylation at the type I promoter (<I>pI</I>) locus of the <I>CIITA</I> gene was markedly increased during DC differentiation and this increase was blocked by IL‐10. We also found that STAT5 bound to the <I>CIITA pI</I> locus during DC differentiation, and the binding was markedly attenuated by TCM or IL‐10. Altogether, these findings suggest that (i) the down‐regulation of MHC class II in tumor microenvironments is most likely attributable to IL‐10 in the TCM and (ii) IL‐10‐mediated MHC class II down‐regulation results from the inhibition of type I CIITA expression. This inhibition is most likely due to blocking of the STAT5‐associated epigenetic modifications of the <I>CIITA pI</I> locus during the entire period of DC differentiation from BM cells, as opposed to a simple inhibition of MHC class II expression at the DC stage.</P>

Improving potency and metabolic stability by introducing an alkenyl linker to pyridine-based histone deacetylase inhibitors for orally available RUNX3 modulators

Song, Doona,Lee, Chulho,Kook, Yoon Jeong,Oh, Soo Jin,Kang, Jong Soon,Kim, Hyun-Jung,Han, Gyoonhee Elsevier 2017 European journal of medicinal chemistry Vol.126 No.-

<P><B>Abstract</B></P> <P>RUNX3, a tumor suppressor, is suppressed in various cancers by abnormal epigenetic changes. Histone deacetylases (HDACs) can deacetylate the lysine residues of RUNX3, followed by degradation via a ubiquitin-mediated pathway. Inhibition of HDAC leads to functional restoration of the RUNX3 protein by epigenetic expression and RUNX3 protein stabilization. We previously reported a series of HDAC inhibitors that restored RUNX3 function. In the present study, we introduced an alkenyl linker group to pyridine-based HDAC inhibitors to improve their potencies and chemical properties. This alkenyl linker made the compounds more rigid, facilitating a better fit than alkyl moieties to the active site of HDAC proteins. Most compounds in this series exhibited potent RUNX activities, HDAC inhibitory activities, and inhibitory activities towards the growth of human cancer cell lines. Notably, one of these derivatives, (<I>E</I>)-3-(1-cinnamyl-2-oxo-1,2-dihydropyridin-3-yl)-<I>N</I>-hydroxyacrylamide (<B>7k</B>), showed excellent properties in a microsomal stability study, in a xenograft study, and in an <I>in vivo</I> pharmacokinetic evaluation. Modulation of RUNX3 therefore results in highly potent and orally available anticancer chemotherapeutic agents.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A new series of RUNX3 modulators showed improved <I>in vitro</I> biological evaluations metabolic stability profiles. </LI> <LI> Compounds exhibited a significant <I>in vivo</I> antitumor activity and pharmacokinetic profiles. </LI> <LI> Compound <B>7k</B> could be a highly potent and orally available anticancer agent. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>A new series of pyridone-core based HDAC inhibitors were synthesized for anticancer chemotherapy through RUNX3 modulation.</P> <P>[DISPLAY OMISSION]</P>

식물의 물부족 스트레스 신호 전달 네트워크에 대한 이해

이재훈(Jae-Hoon Lee) 한국생명과학회 2018 생명과학회지 Vol.28 No.3

식물이 접하는 다양한 환경 스트레스(고온, 저온, 냉해, 고염, 가뭄 등) 중에서 물부족(가뭄) 스트레스는 식물의 생장 및 생산성을 저해하는 가장 주요한 요인으로 보고되어 왔다. 그러므로, 물부족 스트레스에 대한 식물의 반응기작을 명확히 이해하는 것은 물부족 스트레스 저항성이 증가된 유용 작물 개발에 적용될 수 있을 것으로 기대되며, 그 결과 작물 재배 가능 지역의 확대에 기여할 수 있을 것으로 생각된다. 식물의 물부족 스트레스 신호 과정은 크게 식물 호르몬인 앱시스산 의존적인 과정과 비의존적인 과정으로 분류되며, 각각 AREB/ABF, DREB2 전사조절 인자가 주요한 전사 조절 인자로 참여하여 하위 단계 반응 유전자의 발현 조절에 참여한다. 이러한 AREB/ABF, DREB2 의존적인 regulon에 대한 연구를 통해 물부족 스트레스 신호 과정 중 전사 수준의 조절에 대한 규명이 활발히 이루어지고 있다. 해당 신호 과정에는 전사 수준의 조절뿐만 아니라 인산화, 유비퀴틴화와 같은 번역 후 변형 과정 및 염색질 변형에 의해 매개되는 후성유전학적 조절도 연관되어 있다. 본 총설에서는 현재까지 보고된 물부족 스트레스 신호 전달 과정을, 이와 관련되어 보고된 다양한 신호 전달 단백질들의 기능과 연계시켜 알아보고자 한다. 이러한 물부족 스트레스 신호 전달 과정에 대한 명확한 이해는 향후 유용 내건성 작물개발을 위한 이론적 기반 구축에 도움이 될 수 있을 것이라 생각된다. Among a variety of environmental stresses heat, cold, chilling, high salt, drought, and so on exposed to plants, drought stress has been reported as a crucial factor to adversely affect the growth and productivity of plants. Therefore, to understand the mechanism for the drought stress signal transduction pathway in plants is more helpful to develop useful crops that display the enhanced tolerance against drought stress, and to expand crop growing areas. The signal transduction pathway for the drought stress in plants is largely categorized into two types; ABA-dependent pathway and ABA-independent pathway. It has been reported that two transcription factors, AREB/ABF and DREB2, play predominant roles in ABA-dependent and ABA-independent pathways, respectively. In addition to transcriptional regulation mediated by AREB/ABF and DREB2 transcription factors, post-translational modification (such as phosphorylation and ubiquitination) and epigenetic control are importantly involved in the signal transduction for drought stress. In this paper, we review current understanding of signal transduction pathway on drought stress in plants, especially focusing on the biological roles of a variety of signaling components related to drought stress response. Further understanding the mechanism of drought resistance in plants through this review will be useful to establish theoretical basis for developing drought tolerant crops in the future.

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Yi, Sang-Hoon,He, Xi-Biao,Rhee, Yong-Hee,Park, Chang-Hwan,Takizawa, Takumi,Nakashima, Kinichi,Lee, Sang-Hun The Company of Biologists Limited 2014 Development (Cambridge) Vol.141 No.4

<P>Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-associated disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Co-expression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoREST-Hdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.</P>