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Extrachromosomal circular DNA: biogenesis, structure, functions and diseases

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Signal Transduction and Targeted Therapy 2022年第11期7卷 4069-4089页

作者： Ludi Yang Ruobing Jia Tongxin ge shengfang ge Ai Zhuang Peiwei Chai Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai JiaoTong University School of MedicineShanghai20025P.R.China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai20025P.R.China

Extrachromosomal circular DNA(eccDNA),ranging in size from tens to millions of base pairs,is independent of conventional ***,eccDNAs have been considered an unanticipated major source of somatic rearrangements,contributing to genomic remodeling through chimeric circularization and reintegration of circular DNA into the linear *** addition,the origin of eccDNA is considered to be associated with essential chromatin-related events,including the formation of super-enhancers and DNA repair ***,our understanding of the properties and functions of eccDNA has continuously and greatly *** investigations demonstrate that eccDNAs serve as multifunctional molecules in various organisms during diversified biological processes,such as epigenetic remodeling,telomere trimming,and the regulation of canonical signaling ***,its special distribution potentiates eccDNA as a measurable biomarker in many diseases,especially *** loss of eccDNA homeostasis facilitates tumor initiation,malignant progression,and heterogeneous evolution in many *** in-depth understanding of eccDNA provides novel insights for precision cancer *** this review,we summarized the discovery history of eccDNA,discussed the biogenesis,characteristics,and functions of ***,we emphasized the role of eccDNA during tumor pathogenesis and malignant ***,we summarized potential clinical applications that target aberrant eccDNA in multiple diseases.

关键词： chromosomal diseases circular

AAV for gene Therapy in Ocular Diseases:Progress and Prospects

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Research 2024年第3期2023卷 651-670页

作者： Xiaoyu He Yidian Fu Liang Ma Yizheng Yao shengfang ge Zhi Yang Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai JiaoTong University School of MedicineShanghaiChina Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology ShanghaiChina Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience Soochow UniversityClinical Research Center of Neurological DiseaseThe Second Affiliated Hospital of Soochow UniversitySuzhouChina

Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.

关键词： AAV organs treatment

Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs

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Journal of Pharmaceutical Analysis 2023年第2期13卷 127-141页

作者： Qili Liao Jie Yang shengfang ge Peiwei Chai Jiayan Fan Renbing Jia Department of Ophthalmology Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200001China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai200001China

The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome *** dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune ***,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple *** this review,we have updated recent understandings of KMTs'functions and the development of their targeted ***,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune *** addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT *** summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.

关键词： Cancer Epigenetics Histone lysine methyltransferase Epigenetic inhibitors Combined therapeutic strategy Clinical application

Crosstalk between metabolic reprogramming and epigenetics in cancer:updates on mechanisms and therapeutic opportunities

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Cancer Communications 2022年第11期42卷 1049-1082页

作者： Tongxin ge Xiang Gu Renbing Jia shengfang ge Peiwei Chai Ai Zhuang Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011P.R.China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai 200011P.R.China

Reversible,spatial,and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of *** cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous *** dysregulation is a common fea-ture of human cancers,which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene *** epigenome is sensitive to metabolic *** produces various metabolites that are substrates,cofactors,or inhibitors of epigenetic *** in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epige-netic landscape,inducing transcriptional responses to heterogeneous metabolic *** metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional *** modifiers,chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism,facilitating malignant ***,the significance of the close connection between metabolism and epi-genetics in the context of cancer has not been fully ***,it will be constructive to summarize and update the emerging new evidence support-ing this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic *** this review,we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aber-rations and metabolic rewiring to cancer initiation and ***,we highlight the potential therapeutic op

关键词： cancer epigenetics metabolic reprogramming RNA epigenetics therapy

Targeting histone deacetylase suppresses tumor growth through eliciting METTL14-modified m^(6)A RNA methylation in ocular melanoma

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Cancer Communications 2023年第11期43卷 1185-1206页

作者： Ai Zhuang Xiang Gu Tongxin ge Shaoyun Wang shengfang ge Peiwei Chai Renbing Jia Xianqun Fan Department of Ophthalmology Shanghai Ninth People's HospitalShanghai JiaoTong University School of MedicineShanghaiP. R. China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology ShanghaiP. R. China

Background Diversified histone deacetylation inhibitors(HDACis)have demonstrated encouraging outcomes in multiple malignancies.N6-methyladenine(m6A)is the most prevalent messenger RNA modification that plays an essential role in the regulation of ***,an in-depth understanding of the crosstalk between histone acetylation and m6A RNA modifications remains *** study aimed to explore the role of histone acetylation and m6A modifications in the regulation of tumorigenesis of ocular *** Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma *** blot assay was used to detect the global m6A RNA modification ***-omics assays,including RNA-sequencing,cleavage under targets and tagmentation,single-cell sequencing,methylated RNA immunoprecipitation-sequencing(meRIP-seq),and m6A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing(miCLIP-seq),were performed to reveal the mechanisms of HDACis on methyltransferase-like 14(METTL14)and FAT tumor suppressor homolog 4(FAT4)in ocular *** real-time polymerase chain reaction(qPCR),western blotting,and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and *** models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular ***-binding protein immunoprecipitation-qPCR,meRIP-seq,miCLIP-seq,and RNA stability assay were adopted to investigate the mechanism by which m6A levels of FAT4 were *** First,we found that ocular melanoma cells presented vulnerability towards *** triggered the elevation of m6A RNA modification in ocular *** studies revealed that METTL14 served as a downstream candidate for ***14 was silenced by the hypo-histone acetylation status,whereas HDACi restored the normal histone acetylation level of MET

关键词： epigenetics histone deacetylation inhibitors melanoma N6-methyladenine histone-RNA crosstalk

Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4783-4815页

作者： Haoran Ji Chuang Hu Xuhui Yang Yuanhao Liu Guangyu Ji shengfang ge Xiansong Wang Mingsong Wang Department of Thoracic Surgery Shanghai Key Laboratory of Tissue EngineeringShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai 20o011China Department of Ophthalmology Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China

dissemination to distant sites through a series of mechanisms,and it has been proved that lymph node metastasis(LNM)is an essential prognostic indicator in many different types of cancer.

关键词： metastasis cancer. Lymph

A novel clinical artificial intelligence model for disease detection via retinal imaging

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The Innovation 2024年第2期5卷 11-12页

作者： Yidian Fu Liang Ma Sheng Wan shengfang ge Zhi Yang Department of Ophthalmology Ninth People’s HospitalShanghai JiaoTong University School of MedicineShanghai 200011China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai 200011China PCA Lab Key Lab of Intelligent Perception and Systems for High-Dimensional Information of Ministry of EducationNanjing 210000China Jiangsu Key Lab of Image and Video Understanding for Social Security School of Computer Science and EngineeringNanjing University of Science and TechnologyNanjing 210000China

Artificial intelligence(AI)is an emerging field in which computerized systems are used to carry out complex tasks in place of *** AI algorithms have been developed for disease diagnosis and prediction and treatment recommendation across various clinical data types,e.g.,chest X-rays,electrocardiograms,and other radiological images.1 In ophthalmology,particularly,great progress has been made in AI systems over the past *** fundus photography(CFP)and optical coherence tomography(OCT),which are readily available in routine clinical practice,are both mainstream and useful retinal imaging modalities in *** September 2023,the 2023 Lasker-Debakey Clinical Medical Research Award was awarded to three scientists for their work on OCT for accurate retinal disease detection.

关键词： clinical routine diagnosis

EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1187-1203页

作者： Yongyun Li Tianyu Zhu Jie Yang Qianqian Zhang Shiqiong Xu shengfang ge Renbing Jia Jianming Zhang Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200001China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai 200001China National Research Center for Translational Medicine(Shanghai) State Key Laboratory of Medical GenomicsShanghai Institute of HematologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Institute of Translational Medicine Zhangjiang Institute for Advanced StudyShanghai Jiao Tong UniversityShanghai 200240China

Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular *** search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer ***,elevated expression of EHMT2 had been validated in UM ***,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T *** immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of *** transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA *** constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic *** blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key *** summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.

关键词： Uveal melanoma EHMT2 RhoA pathway ARHGAP29 G protein GNAQ GNA11

Epigenetic drug library screening reveals targeting DOT1L abrogates NAD^(+)synthesis by reprogramming H3K79 methylation in uveal melanoma

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Journal of Pharmaceutical Analysis 2023年第1期13卷 24-38页

作者： Xiang Gu Yu Hua Jie Yu Ludi Yang shengfang ge Renbing Jia Peiwei Chai Ai Zhuang Xianqun Fan Department of Ophthalmology Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China

Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in *** histone methylation contributes to the abnormal transcriptome during ***,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains ***,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk ***,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in *** Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its ***,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))***,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of ***,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.

关键词： Histone methylation Metabolic reprogramming Uveal melanoma Transcriptional addiction