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Innovative insights into extrachromosomal circular DNAs in gynecologic tumors and reproduction

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Protein & Cell 2024年第1期15卷 6-20页

作者： Ning Wu Ling Wei Zhipeng Zhu Qiang Liu Kailong Li Fengbiao Mao Jie Qiao xiaolu zhao State Key Laboratory of Female Fertility Promotion Center for Reproductive MedicineDepartment of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijing 100191China National Clinical Research Center for Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China Key Laboratory of Assisted Reproduction(Peking University) Ministry of EducationBeijing 100191China Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology Beijing 100191China Institute of Medical Innovation and Research Peking University Third HospitalBeijing 100191China Cancer Center Peking University Third HospitalBeijing 100191China Department of Biochemistry and Biophysics Beijing Key Laboratory of Protein Posttranslational Modifications and Cell FunctionSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Beijing Advanced Innovation Center for Genomics Beijing 100191China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100191China

Originating but free from chromosomal DNA,extrachromosomal circular DNAs(eccDNAs)are organized in circular form and have long been found in unicellular and multicellular eukaryotes.Their biogenesis and function are poorly understood as they are characterized by sequence homology with linear DNA,for which few detection methods are available.Recent advances in high-throughput sequencing technologies have revealed that eccDNAs play crucial roles in tumor formation,evolution,and drug resistance as well as aging,genomic diversity,and other biological processes,bringing it back to the research hotspot.Several mechanisms of eccDNA formation have been proposed,including the breakage-fusion-bridge(BFB)and translocation-deletion-amplification models.Gynecologic tumors and disorders of embryonic and fetal development are major threats to human reproductive health.The roles of eccDNAs in these pathological processes have been partially elucidated since the first discovery of eccDNA in pig sperm and the double minutes in ovarian cancer ascites.The present review summarized the research history,biogenesis,and currently available detection and analytical methods for eccDNAs and clarified their functions in gynecologic tumors and reproduction.We also proposed the application of eccDNAs as drug targets and liquid biopsy markers for prenatal diagnosis and the early detection,prognosis,and treatment of gynecologic tumors.This review lays theoretical foundations for future investigations into the complex regulatory networks of eccDNAs in vital physiological and pathological processes.

关键词： extrachromosomal circular DNAs gynecologic tumors reproduction liquid biopsy non-invasive prena-tal testing

Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin

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Science China(Life Sciences) 2023年第8期66卷 1786-1799页

作者： Lewei Dong Jian Xiao Shuai Liu Gang Deng Yacheng Liao Beibei Chu xiaolu zhao Bao-Liang Song Jie Luo College of Life Sciences Taikang Center for Life and Medical SciencesHubei Key Laboratory of Cell HomeostasisWuhan UniversityWuhan 430072China College of Veterinary Medicine Henan Agricultural UniversityZhengzhou 450046China

Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.

关键词： cholesterol peroxisome lysosome peroxisomal disorders X-ALD cyclodextrin ABCD1 VLCFA

Enterovirus 713C proteolytically processes the histone H3 N-terminal tail during infection

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Virologica Sinica 2022年第2期37卷 314-317页

作者： Meng Miao Gang Deng Xiaobei Xiong Yang Qiu Wenda Huang Meng Yuan Fei Yu Shimei Bai Xi Zhou xiaolu zhao Hubei Key Laboratory of Cell Homeostasis College of Life SciencesWuhan UniversityWuhan430072China Institute of Biochemistry College of Life Sciences and MedicineZhejiang Sci-Tech UniversityHangzhou310018China Laboratory of RNA Virology Wuhan Institute of VirologyChinese Academy of ScienceWuhan430071China

Dear Editor,Enterovirus 71(EV71)belongs to the genus Enterovirus,family Picornaviridae(Oberste et al.,1999).It was first isolated from patients with central nervous system diseases in California between 1969 and1974(Schmidt et al.,1974)and has spread worldwide(Solomon et al.,2010).EV71 infection usually causes mild,self-limiting hand,foot,and mouth disease in children.Acute EV71 infection may also cause severe polio-like neurological diseases and significant mortality.

关键词： infection diseases

Phylogenomics of non-model ciliates based on transcriptomic analyses

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Protein & Cell 2015年第5期6卷 373-385页

作者： Xiao Chen xiaolu zhao Xiaohui Liu Alan Warren Fangqing zhao Miao Miao College of Life Sciences University of Chinese Academy of Sciences Beijing 100049 China Institute of Evolution & Marine Biodiversity Ocean University of China Qingdao 266003 China Department of Life Sciences Natural History Museum Cromwell Road London SW7 5BD UK Beijing Institutes of Life Science Chinese Academy of Sciences Beijing 100101 China

Ciliates are one of the oldest living eukaryotic unicellular organisms, widely distributed in the waters around the world. As a typical marine oligotrich ciliate, Strombidium sulcatum plays an important role in marine food webs and energy flow. Here we report the first deep se- quencing and analyses of RNA-Seq data from Strombidium sulcatum. We generated 42,640 unigenes with an N50 of 1,451 bp after de novo assembly and removing rRNA, mitochondrial and bacteria contaminants. We employed SPOCS to detect orthologs from S. sulcatum and 17 other ciliates, and then carried out the phyloge- nomic reconstruction using 127 single copy orthologs. In phylogenomic analyses, concatenated trees have similar topological structures with concordance tree on the class level. Together with phylogenetic networks analysis, it aroused more doubts about the placement of Protocruzia, Mesodinium and Myrionecta. While epi- plasmic proteins are known to be related to morphological characteristics, we found the potential relationship between gene expression of epiplasmic proteins and morphological characteristics. This work supports the use of high throughput approaches for phylogenomic analysis as well as correlation analysis between expression level of target genes and morphological characteristics.

关键词： Strombidium protozoa transcriptome,non-model ciliate phylogenomic analysis

Histone methyltransferase TXRl is required for both H3 and H3.3lysine 27 methylation in the well-known ciliated protist Tetrahymena thermophila

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Science China(Life Sciences) 2017年第3期60卷 264-270页

作者： xiaolu zhao Yuanyuan Wang Yurui Wang Yifan Liu Shan Gao Institute of Evolution & Marine Biodiversity Ocean University of China Department of Pathology University of Michigan Laboratory for Marine Biology and Biotechnology Qingdao National Laboratory for Marine Science and Technology

DNA replication elongation is tightly controlled by histone-modifying enzymes.Our previous studies showed that the histone methytransferase TXRl(Tetrahymena Trithorax related protein 1) specifically catalyzes H3K27 monomethylation and affects DNA replication elongation in Tetrahymena thermophila.In this study,we investigated whether TXRl has a substrate preference to the canonical H3 over the replacement variant H3.3.We demonstrated by histone mutagenesis that K27 Q mutation in H3.3further aggravated the replication stress phenotype of K27 Q mutation in canonical H3,supporting H3.3 as a physiologically relevant substrate of TXRl.This result is in apparent contrast to the strong preference for canonical H3 recently reported in Arabidopsis homologues ATXR5 and ATXR6,and further corroborates the role of TXRl in DNA replication.

关键词：嗜热四膜虫原生动物甲基化 DNA复制纤毛相关蛋白组蛋白修饰酶

Proteomics Profiling of Host Cell Response via Protein Expression and Phosphorylation upon Dengue Virus Infection

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Virologica Sinica 2019年第5期34卷 549-562页

作者： Meng Miao Fei Yu Danya Wang Yongjia Tong Liuting Yang Jiuyue Xu Yang Qiu Xi Zhou xiaolu zhao State Key Laboratory of Virology College of Life SciencesWuhan UniversityWuhan 430072China Hubei Key Laboratory of Cell Homeostasis College of Life SciencesWuhan UniversityWuhan 430072China Laboratory of RNA Virology Wuhan Institute of VirologyChinese Academy of ScienceWuhan 430071China

Dengue virus(DENV)infection is a worldwide public health threat.To date,the knowledge about the pathogenesis and progression of DENV infection is still limited.Combining global profiling based on proteomic analysis together with functional verification analysis is a powerful strategy to investigate the interplay between the virus and host cells.In the present study,quantitative proteomics has been applied to evaluate host responses(as indicated by altered proteins and modifications)in human cells(using K562 cell line)upon DENV-2 infection,as DENV-2 spreads most widely among all DENV serotypes.Comparative analysis was performed to define differentially expressed proteins in the infected cells compared to the mock-control,and it revealed critical pathogen-induced changes covering a broad spectrum of host cellular compartments and processes.We also discovered more dramatic changes(>20%,160 regulated phosphoproteins)in protein phosphorylation compared to protein expression(14%,321 regulated proteins).Most of these proteins/phosphoproteins were involved in transcription regulation,RNA splicing and processing,immune system,cellular response to stimulus,and macromolecule biosynthesis.Western blot analysis was also performed to confirm the proteomic data.Potential roles of these altered proteins were discussed.The present study provides valuable large-scale protein-related information for elucidating the functional emphasis of host cell proteins and their post-translational modifications in virus infection,and also provides insight and protein evidence for understanding the general pathogenesis and pathology of DENV.

关键词： Dengue virus(DENV) Quantitative proteomics Virus-host interaction Protein expression Protein phosphorylation

Our recent progress in epigenetic research using the model ciliate, Tetrahymena thermophila

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Marine Life Science & Technology 2019年第1期1卷 4-14页

作者： Ting Cheng Yuanyuan Wang Jie Huang Xiao Chen xiaolu zhao Shan Gao Weibo Song Institute of Evolution and Marine Biodiversity Ocean University of ChinaQingdao 266003China Laboratory for Marine Biology and Biotechnology Qingdao National Laboratory for Marine Science and TechnologyQingdao 266003China Department of Pathology University of MichiganAnn ArborMI 48109USA Department of Genetics and Development Columbia University Medical CenterNew YorkNY 10032USA MOE Key Laboratory of Marine Genetics and Breeding College of Marine Life SciencesOcean University of ChinaQingdao 266003China

Epigenetic research focuses on heritable changes beyond the DNA sequence, which has led to a revolution in biologicalstudies and benefits in many other fields. The well-known model ciliate, Tetrahymena thermophila offers a unique system forepigenetic studies due to its nuclear dimorphism and special mode of sexual reproduction (conjugation), as well as abundantgenomic resources and genetic tools. In this paper, we summarize recent progress made by our research team and collaboratorsin understanding epigenetic mechanisms using Tetrahymena. This includes: (1) providing the first genome-wide basepair-resolution map of DNA N6-methyladenine (6mA) and revealed it as an integral part of the chromatin landscape;(2)dissecting the relative contribution of cis・ and trans- elements to nucleosome distribution by exploring the unique nucleardimorphism of Tetrahymena, (3) demonstrating the epigenetic controls of RNAi-dependent Polycomb repression pathwayson transposable elements, and (4) identifying a new histone monomethyltransferase, TXR1 (Tetrahymena Trithorax 1), thatfacilitates replication elongation through 让s substrate histone H3 lysine 27 monomethylation (H3K27mel).

关键词： Epigenetics Tetrahymena N6-methyladenine(6mA) Nucleosome Transposable elements Histonemethyltransferase TXR1

中国企业所得税的有效税率差异研究——基于财务报表附注数据的分解

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经济科学 2024年第2期 141-158页

作者：刘志阔汪殊逸翁倩茹赵小路复旦大学中国社会主义市场经济研究中心上海财经大学公共经济与管理学院中国海洋大学经济学院

本文基于上市公司财务报表附注数据,对企业所得税有效税率差异的形成因素进行了分解。研究发现如下:第一,近年来企业所得税优惠政策不断推出,其中税基式优惠的增长尤为明显;第二,随着优惠规模的扩大,企业的有效税率普遍下降,但企业间的... 详细信息

本文基于上市公司财务报表附注数据,对企业所得税有效税率差异的形成因素进行了分解。研究发现如下:第一,近年来企业所得税优惠政策不断推出,其中税基式优惠的增长尤为明显;第二,随着优惠规模的扩大,企业的有效税率普遍下降,但企业间的税负差异也随之扩大;第三,税收法定的制度因素对有效税率差异的影响至关重要,其中,适用税率的大小是决定企业有效税率高低的关键因素,而税基调整项中的暂时性差异是有效税率差异的最主要来源。本研究强调,未来的税收政策应更注重效率与公平的权衡,同时考虑企业认知能力的差异,税制设计应避免过于复杂和碎片化。

关键词：企业所得税有效税率差异分解税制设计

Functional analysis of the methyltransferase SMYD in the single-cell model organism Tetrahymena thermophila

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Marine Life Science & Technology 2020年第2期2卷 109-122页

作者： xiaolu zhao Yuan Li Lili Duan Xiao Chen Fengbiao Mao Mina Juma Yifan Liu Weibo Song Shan Gao Institute of Evolution and Marine Biodiversity Ocean University of ChinaQingdao 266003China Department of Pathology University of Michigan.Ann Arbor.MI 48109USA Laboratory for Marine Biology and Biotechnology Qingdao National Laboratory for Marine Science and TechnologyQingdao 266003China

Lysine methylation of histones and non-histones plays a pivotal role in diverse cellular processes.The SMYD(SET and MYND domain)family methyltransferases can methylate various histone and non-histone substrates in mammalian systems,implicated in HSP90 methylation,myofilament organization,cancer inhibition,and gene transcription regulation.To resolve controversies concerning SMYD's substrates and functions,we studied SMYD1(TTHERM_00578660),the only homologue of SMYD in the unicellular eukaryote Tetrahymena thermophila.We epitope-tagged SMYD1,and analyzed its localization and interactome.We also characterized △SMYD1 cells,focusing on the replication and transcription phenotype.Our results show that:(1)SMYD1 is present in both cytoplasm and transcriptionally active macronucleus and shuttles between cytoplasm and macronucleus,suggesting its potential association with both histone and non-histone substrates;(2)SMYD1 is involved in DNA replication and regulates transcription of metabolism-related genes;(3)HSP90 is a potential substrate for SMYD1 and it may regulate target selection of HSP90,leading to pleiotropic effects in both the cytoplasm and the nucleus.

关键词： Tetrahymena thennophila Methyltransferase SMYD DNA replication Transcription HSP90