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Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-β production by mediating H3K79me2/3 methylation in macrophages

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Cellular & Molecular Immunology 2020年第1期17卷 76-84页

作者： Xiang Chen Xingguang Liu Yunkai Zhang Wanwan Huai Qingqing Zhou Sheng Xu Xi Chen Nan Li Xuetao Cao National Key Laboratory of Medical Immunology&Institute of Immunology Second Military Medical UniversityShanghai 200433China Institute of Immunology Zhejiang University School of MedicineHangzhou 310058China Department of Immunology&Center for Immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China

epigenetic modification,including histone modification,precisely controls target gene expression.The posttranscriptional regulation of the innate signaling-triggered production of inflammatory cytokines and type I interferons has been fully elucidated,whereas the roles of histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further explored.Di/tri-methylation modifications of histone 3 lysine 79(H3K79me2/3)have been shown to be associated with gene transcriptional activation.Disruptor of telomeric silencing-1-like(Dot1l)is the only known exclusive H3K79 methyltransferase and regulates the proliferation and differentiation of tumor cells.However,the roles of Dot1l and Dot1l-mediated H3K79 methylation in innate immunity and inflammatory responses remain unclear.Here,we found that H3K79me2/3 modification levels at the Il6 and Ifnb1 promoters,as well as H3K79me2 modification at the Tnfαpromoter,were increased in macrophages activated by Toll-like receptor(TLR)ligands or virus infection.The innate signals upregulated Dot1l expression in macrophages and THP1 cells.Dot1l silencing or a Dot1l inhibitor preferentially suppressed the production of IL-6 and interferon(IFN)-βbut not of TNFαin macrophages and THP1 cells triggered by TLR ligands or virus infection.Dot1l was recruited to the proximal promoter of the Il6 and Ifnb1 but not Tnfαgene and then mediated H3K79me2/3 modification at the Il6 and Ifnb1 promoters,consequently facilitating the transcription and expression of Il6 and Ifnb1.Thus,Dot1l-mediated selective H3K79me2/3 modifications at the Il6 and Ifnb1 promoters are required for the full activation of innate immune responses.This finding adds new insights into the Epigenetic regulation of inflammatory responses and pathogenesis of autoimmune diseases.

关键词： H3K79me2/3 Dot1l Epigenetic regulation IL-6 IFN-β macrophages inflammation

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Natural products as LSD1 inhibitors for cancer therapy

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Acta Pharmaceutica Sinica B 2021年第3期11卷 621-631页

作者： Yuan Fang Chao Yang Zhiqiang Yu Xiaochuan Li Qingchun Mu Guochao Liao Bin Yu Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou 510006China Institute of Innovation&Application Zhejiang Ocean UniversityZhoushcm 316022China School of Pharmaceutical Sciences Southern Medical UniversityGuangzhou 510515China The People’s Hospital of Gaozhou Gaozhou 525200China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase1(LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.

关键词： Epigenetic regulation Histone demethylase Natural products LSD1 inhibitors Drug discovery Cancer therapy

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epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

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Acta Pharmaceutica Sinica B 2020年第5期10卷 723-733页

作者： Xi Chen Xiaohui Pan Wenxin Zhang Hongjie Guo Shuyuan Cheng Qiaojun He Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Immunotherapy strategies targeting the programmed cell death ligand 1(PD-L1)/programmed cell death 1(PD-1)pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer.However,owing to the heterogeneity of tumors and individual immune systems,PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients.Accumulating evidence has shown that an effective response to anti-PD-Ll/anti-PD-1 therapy requires establishing an integrated immune cycle.Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure.Impairments in the immune cycle can be restored by epigenetic modification,including reprogramming the environment of tumor-associated immunity,eliciting an immune response by increasing the presentation of tumor antigens,and by regulating T cell trafficking and reactivation.Thus,a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

关键词： Epigenetic regulation Immune cycle PD-L1PD-1 blockade Cancer Immunotherapy

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The Intronic cis Element SE1 Recruits trans-Acting Repressor Complexes to Repress the Expression of ELONGATED UPPERMOST INTERNODE1 in Rice

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Molecular Plant 2018年第5期11卷 720-735页

作者： Yongyao Xie Yaling Zhang Jingluan Han Jikai Luo Gousi Li Jianle Huang Haibin WU Qingwei Tian Qinlong Zhu Yuanling Chen Yoji Kawano Yao-Guang Liu Letian Chen State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources South China Agricultural University Guangzhou 510642 China Guangdong Provincial Key Laboratory of Protein Function and regulation in Agricultural Organisms South China Agricultural University Guangzhou 510642 China Key Laboratory of Plant Functional Genomics and Biotechnology of Guangdong Provincial Higher Education Institutions South China Agricultural University Guangzhou 510642 China College of Life Sciences South China Agricultural University Guangzhou 510642 China Shanghai Center for Plant Stress Biology Chinese Academy of Sciences Shanghai 201602 China

Plant height has a major effect on grain yield in crops such as rice （Oryza sativa）, and the hormone gibberellic acid （GA） regulates many developmental processes that feed into plant height. Rice ELONGATED UPPERMOST INTERNODE1 （Euil） encodes a GA-deactivating enzyme governing elongation of the uppermost internode. The expression of Euil is finely tuned, thereby maintaining homeostasis of endogenous bioactive GA and producing plants of normal plant height. Here, we identified a dominant dwarf mutant, dEuil, caused by the deletion of an RY motif-containing cis-silencing element （SE1） in the intron of Euil. Detailed genetic and molecular analysis of SE1 revealed that this intronic cis element recruits at least one trans-acting repressor complex, containing the B3 repressors OsVAL2 and OsGD1, the SAP18 corepressor, and the histone deacetylase OsHDA710, to negatively regulate the expression of Euil. This com- plex generates closed chromatin at Euil, suppressing Euil expression and modulating GA homeostasis. Loss of SE1 or dysfunction of the complex components impairs histone deacetylation and H3K27me3 methylation of Euil chromatin, thereby increasing Euil transcription and decreasing bioactive GA, producing dwarfism in rice. Together, our results reveal a novel silencing mechanism in which the intronic cis element SE1 negatively regulates Euil expression via repressor complexes that modulate histone deacetylation and/or methylation.

关键词： B3 domain Epigenetic regulation Euil Histone Deacetylation H3K27me3 Methylation RY Element

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Efficacy of exercise rehabilitation for managing patients with Alzheimer's disease

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Neural Regeneration Research 2024年第10期19卷 2175-2188页

作者： Dan Li Jinning Jia Haibo Zeng Xiaoyan Zhong Hui Chen Chenju Yi Department of Pathology The First Affiliated Hospital of Gannan Medical UniversityGanzhouJiangxi ProvinceChina Department of Pathology Huichang County People’s HospitalGanzhouJiangxi ProvinceChina School of Life Sciences Faculty of ScienceUniversity of Technology SydneyUltimoNSWAustralia Research Center The Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhenGuangdong ProvinceChina Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research ShenzhenGuangdong ProvinceChina Guangdong Provincial Key Laboratory of Brain Function and Disease GuangzhouGuangdong ProvinceChina

Alzheimer's disease(AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low-and middle-income countries.

关键词： Alzheimer's disease cerebrovascular function cognitive function Epigenetic regulation exercise hippocampal neurogenesis mitochondria neuroinflammation neuronal plasticity

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Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease

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Journal of Genetics and Genomics 2016年第10期43卷 587-592页

作者： Lusi Zhang Jie Deng Qian Pan Yan Zhan Jian-Bing Fan Kun Zhang Zhuohua Zhang Institute of Precision Medicine The Xiangya Hospital State Key Laboratory of Medical Genetics Xiangya Medical School Central South University Department of Bioengineering University of California at San Diego Anchor Dx Corporation International Bio-island

Parkinson disease（PD） is a progressive neurodegenerative movement disorder. Both environmental and genetic factors play important roles in PD etiology. A number of environmental toxins cause parkinsonism in human and animal models. Genetic studies of rare early onset familial PD cases resulted in identification of disease-linked mutations in multiple genes. Nevertheless, the potential interaction between environment and genetics in PD pathogenesis remains largely unknown. We hypothesized that environmental factors induce abnormal Epigenetic regulation that is involved in the pathogenesis of both familial and sporadic PD. We determined the global methylation status of 80,000e110,000 Cp G sites in each of the five sporadic PD patient brains and five age and postmodern interval matched control brains utilizing bisulfite padlock sequencing. Multiple genes involved in neurogenesis, particularly the ones in the Wnt signaling pathway, were hypermethylated in PD brains compared to their matched control brains. Consistent with the DNA methylation changes, marked reduction of protein expression was observed for four Wnt and neurogenesis related genes（FOXC1, NEURG2, SPRY1, and CTNNB1） in midbrain dopaminergic（DA） neurons of PD. The treatment of low concentration of 1-methyl-4-phenylpyridinium（MPPt） for cells resulted in downregulation of Wnt related genes. The study revealed an important link between the epigenetic disregulation of Wnt signaling and the pathogenesis and progression of PD.

关键词： Epigenetic regulation Neurodegenerative diseases Environmental toxins Neurogenesis

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Control of Leaf Senescence by an MeOH- Jasmonates Cascade that Is epigenetically Regulated by OsSRT1 in Rice

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Molecular Plant 2016年第10期9卷 1366-1378页

作者： ChuanYing Fang Hua Zhang Jian Wan YangYang Wu Kang Li Cheng Jin Wei Chen ShouChuang Wang WenSheng Wang HaiWei Zhang Pan Zhang Fei Zhang LiangHuan Qu Xianqing Liu Dao-Xiu Zhou Jie Luo National Key Laboratory of Crop Genetic Improvement and National Center of Plant Gene Research (Wuhan) Huazhong Agricultural University Wuhan 430070China Institute for Nutritional Sciences Shanghai Institutes for Biological Sciences Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai200031 China College of Life Science and Technology Huazhong Agricultural University Wuhan 430070 China Institute of Plant Sciences Paris-Saclay Universite Paris-sud 11 Orsay 91405 France

Although considerable progress has been made in identifying the genes regulating accumulation of hormones that are involved in leaf senescence, only a few studies have focused on natural variations in jasmonates content and much less on the underlying genetic basis. Moreover, the Epigenetic regulation of jasmonate-mediated leaf senescence remains largely unknown, in this study, we carried out metabolic profiling of a worldwide collection of rice accessions and demonstrated that there are substantial variations in jasmonate levels among these accessions. A subsequent metabolite-based genornewide association study identified candidates for two major quantitative genes （QTGs）, OsPME1 and OsTSD2, affecting the content of jasmonates. Further investigations using a series of relevant mutants and transgenic lines revealed the MeOH-jasmonata cascade plays an important role in regulating leaf senescence. Moreover, we showed that OsSRT1, one of the two Sir2 （silent information regugator 2） homologs in rice, negatively regulates leaf senescence by repressing expression of the biosynthetic genes of this metabolic cascade and at least particiaUy through histone H3K9 deacetylation of OsPME1. Taken together, our results indicate that the MeOH-jasmonates cascade and its Epigenetic regulation are crucial for controlling leaf senescence process in rice.

关键词： MeOH-jasmonate cascade leaf senescence natural variation Epigenetic regulation

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PRCl Marks the Difference in Plant PcG Repression

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Molecular Plant 2014年第3期7卷 459-471页

作者： Myriam Calonje Institute of Plant Biochemistry and Photosynthesis (IBVF) Avenida America Vespucio 49 Isla de La Cartuja 41092 Seville Spain

From mammals to plants, the Polycomb Group （PcG） machinery plays a crucial role in maintaining the repres- sion of genes that are not required in a specific differentiation status. However, the mechanism by which PeG machinery mediates gene repression is still largely unknown in plants. Compared to animals, few PcG proteins have been identi- fied in plants, not only because just some of these proteins are clearly conserved to their animal counterparts, but also because some PcG functions are carried out by plant-specific proteins, most of them as yet uncharacterized. For a long time, the apparent lack of Polycomb Repressive Complex （PRC）I components in plants was interpreted according to the idea that plants, as sessile organisms, do not need a long-term repression, as they must be able to respond rapidly to environmental signals; however, some PRC1 components have been recently identified, indicating that this may not be the case. Furthermore, new data regarding the recruitment of PcG complexes and maintenance of PcG repression in plants have revealed important differences to what has been reported so far. This review highlights recent progress in plant PcG function, focusing on the role of the putative PRC1 components.

关键词： Polycomb Group Epigenetic regulation PRC1 gene repression H2A monoubiquitination chromatin compaction.

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Cellular, physiological and pathological aspects of the long non-coding RNA NEAT1

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Frontiers in Biology 2016年第6期11卷 413-426页

作者： Pang-Kuo Lo Benjamin Wolfson Qun Zhou Department of Biochemistry and Molecular Biology Greenebaum Cancer Center University of Maryland School of Medicine BaltimoreMD 21201 USA

BACKGROUND： The majority of mammalian genomes have been found to be transcribed into non-coding RNAs. One category of non-coding RNAs is classified as long non-coding RNAs （lncRNAs） based on their transcript sizes larger than 200 nucleotides. Growing evidence has shown that lncRNAs are not junk transcripts and play regulatory roles in multiple aspects of biological processes. Dysregulation of lncRNA expression has also been linked to diseases, in particular cancer. Therefore, studies of lncRNAs have attracted significant interest in the field of medical research. Nuclear enriched abundant transcript 1 （NEAT1）, a nuclear lncRNA, has recently emerged as a key regulator involved in various cellular processes, physiological responses, developmental processes, and disease development and progression. OBJECTIVE： This review will summarize and discuss the most recent findings with regard to the roles of NEAT1 in the function of the nuclear paraspeckle, cellular pathways, and physiological responses and processes. Particularly, the most recently reported studies regarding the pathological roles of deregulated NEAT1 in cancer are highlighted in this review. METHODS： We performed a systematic literature search using the Pubmed search engine. Studies published over the past 8 years （between January 2009 and August 2016） were the sources of literature review. The following keywords were used：＂Nuclear enriched abundant transcript 1,＂＂NEATI,＂ and ＂paraspeckles.＂ RESULTS： The Pubmed search identified 34 articles related to the topic of the review. Among the identified literature, 13 articles report findings related to cellular functions of NEAT1 and eight articles are the investigations of physiological functions of NEAT1. The remaining 13 articles are studies of the roles of NEAT1 in cancers. CONCLUSION： Recent advances in NEAT1 studies reveal the multifimctional roles of NEAT1 in various biological processes, which are beyond its role in nuclear paraspeckles. Recent studies also indicate that dysregulation of NEAT1 function

关键词： long non-coding RNAs （lncRNAs） nuclear enriched abundant transcript 1 （NEAT1） paraspeckles microRNAs（miRNAs） Epigenetic regulation cancer

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Histone Variants in Development and Diseases

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Journal of Genetics and Genomics 2013年第7期40卷 355-365页

作者： Ping Chen Jicheng Zhao Guohong Li National Laboratory of Biomacromolecules.Institute of Biophysics Chinese Academy of Sciences

Eukaryotic genomic DNA is highly packaged into chromatin by histones to fit inside the nucleus. Other than the bulk packaging role of canonical histones with an expression peak at S phase and replication-coupled deposition, different histone variants have evolved distinct regulatory mechanisms for their expression, deposition and functional implications. The diversity of histone variants results in structural plasticity of chromatin and highlights functionally distinct chromosomal domain, which plays critical roles in development from a fertilized egg into a complex organism, as well as in aging and diseases. However, the mechanisms of this fundamental process are poorly understood so far. It is of particular interest to investigate how the variants are incorporated into chromatin and mark specific chromatin states to regulate gene expression, and how they are involved in development and diseases. In this review, we focus on recent progress in studies of Epigenetic regulation of three extensively investigated variants including H2A.Z, macroH2A and H3.3, and their functional implications in development and diseases.

关键词： Histone variant Higher-order chromatin structure Epigenetic regulation Development Diseases

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