N6-methyl-adenosine （m6A） is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m6A methylation remains largely unknown. Several indepen...N6-methyl-adenosine （m6A） is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m6A methylation remains largely unknown. Several independent lines of evidence suggest that the dynamic regulation ofm6A may have a profound impact on gene expression regulation. The m6A modification is catalyzed by an unidentified methyltransferase complex containing at least one subunit methyltransferase like 3 （METTL3）. m6A modification on messenger RNAs （mRNAs） mainly occurs in the exonic regions and 3＇-untranslated region （3＇-UTR） as revealed by high-throughput m6A-seq. One significant advance in m6A research is the recent discovery of the first two m6A RNA demethylases fat mass and obesity- associated （FTO） gene and ALKBH5, which catalyze m6A demethylation in an cx-ketoglutarate （a-KG）- and FeZ ＋ -dependent manner. Recent studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play important roles in many biological processes, ranging from devel- opment and metabolism to fertility. Moreover, perturbation of activities of these enzymes leads to the disturbed expression of thousands of genes at the cellular level, implicating a regulatory role ofm6A in RNA metabolism. Given the vital roles of DNA and histone methylations in epigenetic regulation of basic life processes in mammals, the dynamic and reversible chemical m6A modification on RNA may also serve as a novel epigenetic marker of profound biological significances.展开更多
N6-methyladenosine (m6A),catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14,is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However,the roles a...N6-methyladenosine (m6A),catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14,is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However,the roles and precise mechanisms of m6A modification in regulating neuronal development and adult neurogenesis remain unclear. Here,we examined the function of Mettl3,the key component of the complex,in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced m6A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neu-ronal development and skewed the differentiation of aNSCs more toward glial lineage,but also affected the morphological maturation of newborn neurons in the adult brain. m6A immunoprecip-itation combined with deep sequencing (MeRIP-seq) revealed that m6A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically,m6A was present on the transcripts of histone methyltransferase Ezh2,and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively,our results uncover a crosstalk between RNA and histone modifica-tions and indicate that Mettl3-mediated m6A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.展开更多
Non-small-cell lung cancer （NSCLC）, the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymetbylcy...Non-small-cell lung cancer （NSCLC）, the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymetbylcytosine （ShmC） signatures in circulating cell-free DNA （cfDNA） that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminat- ing tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sensitive and reliable method to map genome-wide 5hmC in the cfDNA of Chinese NSCLC patients and detected a significant 5hmC gain in both the gene bodies and promoter regions in the blood samples from tumor patients compared with healthy controls. Specifically, we identi- fied six potential biomarkers from 66 patients and 67 healthy controls （mean decrease accuracy 〉 3.2, P 〈 3.68E-19） using machine-learning-based tumor classifiers with high accuracy. Thus, the unique signature of 5hmC in tumor patient＇s cfDNA identified in our study may provide valuable information in facilitating the development of new diagnostic and therapeutic modalities for NSCLC.展开更多
The unicellular green alga Chlamydomonas reinhardtii(hereafter Chlamydomonas)possesses both plant and animal attributes,and it is an ideal model organism for studying fundamental processes such as photosynthesis,sexua...The unicellular green alga Chlamydomonas reinhardtii(hereafter Chlamydomonas)possesses both plant and animal attributes,and it is an ideal model organism for studying fundamental processes such as photosynthesis,sexual reproduction,and life cycle.N^(6)-methyladenosine(m^(6)A)is the most prevalent mRNA modification,and it plays important roles during sexual reproduction in animals and plants.However,the pattern and function of m^(6)A modification during the sexual reproduction of Chlamydomonas remain unknown.Here,we performed transcriptome and methylated RNA immunoprecipitation sequencing(MeRIP-seq)analyses on six samples from different stages during sexual reproduction of the Chlamydomonas life cycle.The results show that m^(6)A modification frequently occurs at the main motif of DRAC(D=G/A/U,R=A/G)in Chlamydomonas mRNAs.Moreover,m^(6)A peaks in Chlamydomonas mRNAs are mainly enriched in the 30 untranslated regions(30 UTRs)and negatively correlated with the abundance of transcripts at each stage.In particular,there is a significant negative correlation between the expression levels and the m^(6)A levels of genes involved in the microtubule-associated pathway,indicating that m^(6)A modification influences the sexual reproduction and the life cycle of Chlamydomonas by regulating microtubule-based movement.In summary,our findings are the first to demonstrate the distribution and the functions of m^(6)A modification in Chlamydomonas mRNAs and provide new evolutionary insights into m^(6)A modification in the process of sexual reproduction in other plant organisms.展开更多
The effects of the introduction of Ce to La（1-x）CexFe（11.5）Si（1.5） alloys on 1：13 phase formation mechanism,the first-order magnetic phase transition strengthening characteristics,and magnetocaloric property we...The effects of the introduction of Ce to La（1-x）CexFe（11.5）Si（1.5） alloys on 1：13 phase formation mechanism,the first-order magnetic phase transition strengthening characteristics,and magnetocaloric property were studied,respectively.The results show that the formation mechanisms of 1：13 and La Fe Si phases in La（1-x）CexFe（11.5）Si（1.5） alloys are the same as those of Ce2Fe（17） and CeFe2 phases in Ce–Fe binary system,respectively.The substitution of Ce in 1：13 phase which is limited can make the first-order magnetic phase transition characteristics strengthen,which can make thermal and magnetic hysteresis increase,the temperature interval of temperatureinduced phase transition decrease,and the critical magnetic field of field-induced magnetic phase transition（HC）increase,respectively.Owing to the lattice shrink of 1：13phase with the increase in Ce content,the Curie temperatures（TC） show a linear decrease.The maximum change in magnetic entropy gradually increases due to the decrease in temperature interval of temperature-induced phase transition,but the relative cooling capacities are all about80 Jákg-1at magnetic field of 2 T.展开更多
After implantation,complex and highly specialized molecular events render functionally distinct organ formation,whereas how the epigenome shapes organ-specific development remains to be fully elucidated.Here,nano-hmC-...After implantation,complex and highly specialized molecular events render functionally distinct organ formation,whereas how the epigenome shapes organ-specific development remains to be fully elucidated.Here,nano-hmC-Seal,RNA bisulfite sequencing(RNA-BisSeq),and RNA sequencing(RNA-Seq)were performed,and the first multilayer landscapes of DNA 5-hydroxymethylcytosine(5hmC)and RNA 5-methylcytosine(m^(5)C)epigenomes were obtained in the heart,kidney,liver,and lung of the human foetuses at 13-28 weeks with 123 samples in total.We identified 70,091 and 503 organ-and stage-specific differentially hydroxymethylated regions(DhMRs)and m^(5)C-modified mRNAs,respectively.The key transcription factors(TFs),T-box transcription factor 20(TBX20),paired box 8(PAX8),krueppel-like factor 1(KLF1),transcription factor 21(TCF21),and CCAAT enhancer binding protein beta(CEBPB),specifically contribute to the formation of distinct organs at different stages.Additionally,5hmC-enriched Alu elements may participate in the regulation of expression of TF-targeted genes.Our integrated studies reveal a putative essential link between DNA modification and RNA methylation,and illustrate the epigenetic maps during human foetal organogenesis,which provide a foundation for an in-depth understanding of the epigenetic mechanisms underlying early development and birth defects.展开更多
RNA modifications affect many biological processes and physiological diseases.The 5-methylcytosine(m^(5)C)modification regulates the progression of multiple tumors.However,its characteristics and functions in hepatoce...RNA modifications affect many biological processes and physiological diseases.The 5-methylcytosine(m^(5)C)modification regulates the progression of multiple tumors.However,its characteristics and functions in hepatocellular carcinoma(HCC)remain largely unknown.Here,we found that HCC tissues had a higher m^(5)C methylation level than the adjacent normal tissues.Transcriptome analysis revealed that the hypermethylated genes mainly participated in the phosphokinase signaling pathways,such as the Ras and PI3K-Akt pathways.The m^(5)C methyltransferase NSUN2 was highly expressed in HCC tissues.Interestingly,the expression of many genes was positively correlated with the expression of NSUN2,including GRB2,RNF115,AATF,ADAM15,RTN3,and HDGF.Real-time PCR assays further revealed that the expression of the mRNAs of GRB2,RNF115,and AATF decreased significantly with the down-regulation of NSUN2 expression in HCC cells.Furthermore,NSUN2 could regulate the cellular sensitivity of HCC cells to sorafenib via modulating the Ras signaling pathway.Moreover,knocking down NSUN2 caused cell cycle arrest.Taken together,our study demonstrates the vital role of NSUN2 in the progression of HCC.展开更多
Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)positively affect the initial control of non-small cell lung cancer(NSCLC).Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful...Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)positively affect the initial control of non-small cell lung cancer(NSCLC).Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment.However,the mechanisms that control the resistance of EGFR-TKIs remain largely unknown.RNA structures have widespread and crucial functions in many biological regulations;however,the functions of RNA structures in regulating cancer drug resistance remain unclear.Here,the psoralen analysis of RNA interactions and structures(PARIS)method is used to establish the higher-order RNA structure maps of EGFRTKIs-resistant and-sensitive cells of NSCLC.Our results show that RNA structural regions are enriched in untranslated regions(UTRs)and correlate with translation efficiency(TE).Moreover,yrdC N6-threonylcarbamoyltransferase domain containing(YRDC)promotes resistance to EGFR-TKIs.RNA structure formation in YRDC 30 UTR suppresses embryonic lethal abnormal vision-like 1(ELAVL1)binding,leading to EGFR-TKI sensitivity by impairing YRDC translation.A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide(ASO)to perturb the interaction between RNA and protein.Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and ...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and global economic burden.The recurring global wave of infections has been exacerbated by growing variants of SARS-CoV-2.In this study,the virological characteristics of the original SARS-CoV-2 strain and its variants of concern(VOCs;including Alpha,Beta,and Delta)in vitro,as well as differential transcriptomic landscapes in multiple organs(lung,right ventricle,blood,cerebral cortex,and cerebellum)from the infected rhesus macaques,were elucidated.The original strain of SARS-CoV-2 caused a stronger innate immune response in host cells,and its VOCs markedly increased the levels of subgenomic RNAs,such as N,Orf9b,Orf6,and Orf7ab,which are known as the innate immune antagonists and the inhibitors of antiviral factors.Intriguingly,the original SARS-CoV-2 strain and Alpha variant induced larger alteration of RNA abundance in tissues of rhesus monkeys than Beta and Delta variants did.Moreover,a hyperinflammatory state and active immune response were shown in the right ventricles of rhesus monkeys by the up-regulation of inflammation-and immune-related RNAs.Furthermore,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected individuals.Collectively,these data provide insights into the pathogenesis of COVID-19 at the early stage of infection by the original SARS-CoV-2 strain and its VOCs.展开更多
During mammalian preimplantation development,a totipotent zygote undergoes several cell cleavages and two rounds of cell fate determination,ultimately forming a mature blastocyst.Along with compaction,the establishmen...During mammalian preimplantation development,a totipotent zygote undergoes several cell cleavages and two rounds of cell fate determination,ultimately forming a mature blastocyst.Along with compaction,the establishment of apicobasal cell polarity breaks the symmetry of an embryo and guides subsequent cell fate choice.Although the lineage segregation of the inner cell mass(ICM)and trophectoderm(TE)is the first symbol of cell differentiation,several molecules have been shown to bias the early cell fate through their inter-cellular variations at much earlier stages,including the 2-and 4-cell stages.The underlying mechanisms of early cell fate determination have long been an important research topic.In this review,we summarize the molecular events that occur during early embryogenesis,as well as the current understanding of their regulatory roles in cell fate decisions.Moreover,as powerful tools for early embryogenesis research,single-cell omics techniques have been applied to both mouse and human preimplantation embryos and have contributed to the discovery of cell fate regulators.Here,we summarize their applications in the research of preimplantation embryos,and provide new insights and perspectives on cell fate regulation.展开更多
Background:Health care workers are at the frontline in the fight against infectious disease,and as a result are at a high risk of infection.During the 2014-2015 Ebola outbreak in West Africa,many health care workers c...Background:Health care workers are at the frontline in the fight against infectious disease,and as a result are at a high risk of infection.During the 2014-2015 Ebola outbreak in West Africa,many health care workers contracted Ebola,some fatally.However,no members of the Chinese Anti-Ebola medical team,deployed to provide vital medical care in Liberia were infected.This study aims to understand how this zero infection rate was achieved.Methods:Data was collected through 15 in-depth interviews with participants from the People’s Liberation Army of China medical team which operated the Chinese Ebola Treatment Center from October 2014 to January 2015 in Liberia.Data were analysed using systematic framework analysis.Results:This study found numerous bio-psycho-socio-behavioural risk factors that directly or indirectly threatened the health of the medical team working in the Chinese Ebola Treatment Center.These factors included social and emotional stress caused by:(1)the disruption of family and social networks;(2)adapting to a different culture;(3)and anxiety over social and political unrest in Liberia.Exposure to Ebola from patients and local co-workers,and the incorrect use of personal protective equipment due to fatigue was another major risk factor.Other risk factors identified were:(1)shortage of supplies;(2)lack of trained health personnel;(3)exposure to contaminated food and water;(4)and long working hours.Comprehensive efforts were taken throughout the mission to mitigate these factors.Every measure was taken to prevent the medical team’s exposure to the Ebola virus,and to provide the medical team with safe,comfortable working and living environments.There were many challenges in maintaining the health safety of the team,such as the limited capability of the emergency command system(the standardized approach to the command,control,and coordination of an emergency response),and the lack of comprehensive international protocols for dealing with emerging infectious disease pandemics.Conclusions:The comprehe展开更多
Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic i...Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction （PCR） and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication （FLT3/ITD） and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 （19.7%） of 76 subjects, and NPM1 mutation in 20 （26.3%） subjects. Seven （9.2%） cases were positive for both FLT3/ITD and NPM1 mutations Significantly more FLT3/ITD aberration was detected in subjects with French-American-British （FAB） M1 （42.8%）. NPM1 mutation was frequently detected in subjects with M5 （47.1%） and infrequently in subjects with M2 （11.1%）. FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITD- positive group had a lower complete remission （CR） rate （53.3% vs. 83.6%）. Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival （OS） and relapse-free survival （RFS）. The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group （P=0.069）. Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.展开更多
AIM:To study the diagnostic value of immunoglobulin heavy chain(IgH)and T-cell receptorγ (TCR-γ)gene monoclonal rearrangements in primary gastric lymphoma(PGL).METHODS:A total of 48 patients with suspected PGL at ou...AIM:To study the diagnostic value of immunoglobulin heavy chain(IgH)and T-cell receptorγ (TCR-γ)gene monoclonal rearrangements in primary gastric lymphoma(PGL).METHODS:A total of 48 patients with suspected PGL at our hospital were prospectively enrolled in this study from January 2009 to December 2011.The patients were divided into three groups(a PGL group,a gastric linitis plastica group,and a benign gastric ulcer group)based on the pathological results(gastric mucosal specimens obtained by endoscopy or surgery)and follow-up.Endoscopic ultrasonography(EUS)and EUSguided biopsy were performed in all the patients.The tissue specimens were used for histopathological examination and for IgH and TCR-γ gene rearrangement polymerase chain reaction analyses.RESULTS:EUS and EUS-guided biopsy were successfully performed in all 48 patients.In the PGL group(n=21),monoclonal IgH gene rearrangements were detected in 14(66.7%)patients.A positive result for each set of primers was found in 12(57.1%),8(38.1%),and 4(19.0%)cases using FR1/JH,FR2/JH,and FR3/JH primers,respectively.Overall,12(75%)patients with mucosal-associated lymphoid tissue lymphoma(n=16)and 2(40%)patients with diffuse large B-cell lymphoma(n=5)were positive for monoclonal IgH gene rearrangements.No patients in the gastric linitis plastica group(n=17)and only one(10%)patient in the benign gastric ulcer group(n=10)were positive for a monoclonal IgH gene rearrangement.No TCRgene monoclonal rearrangements were detected.The sensitivity of monoclonal IgH gene rearrangements was 66.7%for a PGL diagnosis,and the specificity was96.4%.In the PGL group,8(100%)patients with stage IIE PGL(n=8)and 6(46.1%)patients with stage IE PGL(n=13)were positive for monoclonal IgH gene rearrangements.CONCLUSION:IgH gene rearrangements may be associated with PGL staging and may be useful for the diagnosis of PGL and for differentiating between PGL and gastric linitis plastica.展开更多
基金supported by the China 973 programs (Grant No.2011CB510103 and 2012CB518302) awarded to YGYthe CAS Innovation Program for Young Scientists to YN+1 种基金the CAS "100-talents" Professor Program to YGYthe National Natural Science Foundation of China (Grant No. 30900724 and 81071648) to YN
文摘N6-methyl-adenosine （m6A） is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m6A methylation remains largely unknown. Several independent lines of evidence suggest that the dynamic regulation ofm6A may have a profound impact on gene expression regulation. The m6A modification is catalyzed by an unidentified methyltransferase complex containing at least one subunit methyltransferase like 3 （METTL3）. m6A modification on messenger RNAs （mRNAs） mainly occurs in the exonic regions and 3＇-untranslated region （3＇-UTR） as revealed by high-throughput m6A-seq. One significant advance in m6A research is the recent discovery of the first two m6A RNA demethylases fat mass and obesity- associated （FTO） gene and ALKBH5, which catalyze m6A demethylation in an cx-ketoglutarate （a-KG）- and FeZ ＋ -dependent manner. Recent studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play important roles in many biological processes, ranging from devel- opment and metabolism to fertility. Moreover, perturbation of activities of these enzymes leads to the disturbed expression of thousands of genes at the cellular level, implicating a regulatory role ofm6A in RNA metabolism. Given the vital roles of DNA and histone methylations in epigenetic regulation of basic life processes in mammals, the dynamic and reversible chemical m6A modification on RNA may also serve as a novel epigenetic marker of profound biological significances.
基金supported in part by the International Collaboration Program of the Ministry of Science and Technology of China (Grant No. YS2017YFGH001214)the National Natural Science Foundation of China (Grant Nos. 31771395 and 31571518)+6 种基金the National Key R&D Program of China (Grant No. 2016YFC0900400)supported by the National Natural Science Foundation of China (Grant No. 31770872)the Youth Innovation Promotion Association (Grant No. CAS2018133)the National Key R&D Program of China, Stem Cell and Translational Research (Grant No. 2018YFA0109700)supported in part by the National Key R&D Program of China (Grant No. 2017YFC1001703)the Key R&D Program of Zhejiang Province (Grant No. 2017C03009)Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (2016-6), China
文摘N6-methyladenosine (m6A),catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14,is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However,the roles and precise mechanisms of m6A modification in regulating neuronal development and adult neurogenesis remain unclear. Here,we examined the function of Mettl3,the key component of the complex,in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced m6A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neu-ronal development and skewed the differentiation of aNSCs more toward glial lineage,but also affected the morphological maturation of newborn neurons in the adult brain. m6A immunoprecip-itation combined with deep sequencing (MeRIP-seq) revealed that m6A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically,m6A was present on the transcripts of histone methyltransferase Ezh2,and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively,our results uncover a crosstalk between RNA and histone modifica-tions and indicate that Mettl3-mediated m6A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.
基金supported by grants from the Ministry of Science and Technology of China (Grant No. 2016YFC0900300)National Natural Science Foundation of China (Grant Nos. 31670895, U1504831, 31430022, 31670824, 31400672, and 81703598)+3 种基金Major Science and Technology Project of Henan Province (Grant No. 161100310100)Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB14030300)Foundation for University Young Key Teacher of Henan Province (Grant No. 2015GGJS-162)Science and Technology Project of Henan Province (Grant No.162102310199), China
文摘Non-small-cell lung cancer （NSCLC）, the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymetbylcytosine （ShmC） signatures in circulating cell-free DNA （cfDNA） that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminat- ing tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sensitive and reliable method to map genome-wide 5hmC in the cfDNA of Chinese NSCLC patients and detected a significant 5hmC gain in both the gene bodies and promoter regions in the blood samples from tumor patients compared with healthy controls. Specifically, we identi- fied six potential biomarkers from 66 patients and 67 healthy controls （mean decrease accuracy 〉 3.2, P 〈 3.68E-19） using machine-learning-based tumor classifiers with high accuracy. Thus, the unique signature of 5hmC in tumor patient＇s cfDNA identified in our study may provide valuable information in facilitating the development of new diagnostic and therapeutic modalities for NSCLC.
基金supported by the National Key R&D Program of China(Grant Nos.2019YFA0904600,2018YFA0801200,and 2021YFA0910800)the National Natural Science Foundation of China(Grant Nos.31870217 and 91940304).
文摘The unicellular green alga Chlamydomonas reinhardtii(hereafter Chlamydomonas)possesses both plant and animal attributes,and it is an ideal model organism for studying fundamental processes such as photosynthesis,sexual reproduction,and life cycle.N^(6)-methyladenosine(m^(6)A)is the most prevalent mRNA modification,and it plays important roles during sexual reproduction in animals and plants.However,the pattern and function of m^(6)A modification during the sexual reproduction of Chlamydomonas remain unknown.Here,we performed transcriptome and methylated RNA immunoprecipitation sequencing(MeRIP-seq)analyses on six samples from different stages during sexual reproduction of the Chlamydomonas life cycle.The results show that m^(6)A modification frequently occurs at the main motif of DRAC(D=G/A/U,R=A/G)in Chlamydomonas mRNAs.Moreover,m^(6)A peaks in Chlamydomonas mRNAs are mainly enriched in the 30 untranslated regions(30 UTRs)and negatively correlated with the abundance of transcripts at each stage.In particular,there is a significant negative correlation between the expression levels and the m^(6)A levels of genes involved in the microtubule-associated pathway,indicating that m^(6)A modification influences the sexual reproduction and the life cycle of Chlamydomonas by regulating microtubule-based movement.In summary,our findings are the first to demonstrate the distribution and the functions of m^(6)A modification in Chlamydomonas mRNAs and provide new evolutionary insights into m^(6)A modification in the process of sexual reproduction in other plant organisms.
基金financially supported by the National Natural Science Foundation of China(No.51176050)the Research Projects in Sichuan Province Education Office(No.12ZB073)
文摘The effects of the introduction of Ce to La（1-x）CexFe（11.5）Si（1.5） alloys on 1：13 phase formation mechanism,the first-order magnetic phase transition strengthening characteristics,and magnetocaloric property were studied,respectively.The results show that the formation mechanisms of 1：13 and La Fe Si phases in La（1-x）CexFe（11.5）Si（1.5） alloys are the same as those of Ce2Fe（17） and CeFe2 phases in Ce–Fe binary system,respectively.The substitution of Ce in 1：13 phase which is limited can make the first-order magnetic phase transition characteristics strengthen,which can make thermal and magnetic hysteresis increase,the temperature interval of temperatureinduced phase transition decrease,and the critical magnetic field of field-induced magnetic phase transition（HC）increase,respectively.Owing to the lattice shrink of 1：13phase with the increase in Ce content,the Curie temperatures（TC） show a linear decrease.The maximum change in magnetic entropy gradually increases due to the decrease in temperature interval of temperature-induced phase transition,but the relative cooling capacities are all about80 Jákg-1at magnetic field of 2 T.
基金supported by the National Key R&D Program of China(Grant Nos.2019YFA0110900,2019YFA0802202,2019YFA0802200 and 2020YFA0803401)the National Natural Science Foundation of China(Grant Nos.31870817 and 32170819)+2 种基金the Scientific and Technological Innovation Talent Project of Universities of Henan Province,China(Grant No.20HASTIT045)the Shanghai Municipal Science and Technology Major Project,China(Grant No.2017SHZDZX01)the China Postdoctoral Science Foundation(Grant No.2021M692927).
文摘After implantation,complex and highly specialized molecular events render functionally distinct organ formation,whereas how the epigenome shapes organ-specific development remains to be fully elucidated.Here,nano-hmC-Seal,RNA bisulfite sequencing(RNA-BisSeq),and RNA sequencing(RNA-Seq)were performed,and the first multilayer landscapes of DNA 5-hydroxymethylcytosine(5hmC)and RNA 5-methylcytosine(m^(5)C)epigenomes were obtained in the heart,kidney,liver,and lung of the human foetuses at 13-28 weeks with 123 samples in total.We identified 70,091 and 503 organ-and stage-specific differentially hydroxymethylated regions(DhMRs)and m^(5)C-modified mRNAs,respectively.The key transcription factors(TFs),T-box transcription factor 20(TBX20),paired box 8(PAX8),krueppel-like factor 1(KLF1),transcription factor 21(TCF21),and CCAAT enhancer binding protein beta(CEBPB),specifically contribute to the formation of distinct organs at different stages.Additionally,5hmC-enriched Alu elements may participate in the regulation of expression of TF-targeted genes.Our integrated studies reveal a putative essential link between DNA modification and RNA methylation,and illustrate the epigenetic maps during human foetal organogenesis,which provide a foundation for an in-depth understanding of the epigenetic mechanisms underlying early development and birth defects.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.32170594 and 31870809)the Province and Ministry Coconstruction Major Program of Medical Science and Technique Foundation of Henan Province(Grant No.SBGJ202001007)the Special Fund for Young and Middle School Leaders of Henan Health Commission(Grant No.HNSWJW-2020017),China.
文摘RNA modifications affect many biological processes and physiological diseases.The 5-methylcytosine(m^(5)C)modification regulates the progression of multiple tumors.However,its characteristics and functions in hepatocellular carcinoma(HCC)remain largely unknown.Here,we found that HCC tissues had a higher m^(5)C methylation level than the adjacent normal tissues.Transcriptome analysis revealed that the hypermethylated genes mainly participated in the phosphokinase signaling pathways,such as the Ras and PI3K-Akt pathways.The m^(5)C methyltransferase NSUN2 was highly expressed in HCC tissues.Interestingly,the expression of many genes was positively correlated with the expression of NSUN2,including GRB2,RNF115,AATF,ADAM15,RTN3,and HDGF.Real-time PCR assays further revealed that the expression of the mRNAs of GRB2,RNF115,and AATF decreased significantly with the down-regulation of NSUN2 expression in HCC cells.Furthermore,NSUN2 could regulate the cellular sensitivity of HCC cells to sorafenib via modulating the Ras signaling pathway.Moreover,knocking down NSUN2 caused cell cycle arrest.Taken together,our study demonstrates the vital role of NSUN2 in the progression of HCC.
基金supported by grants from the Province and Ministry Coconstruction Major Program of Medical Science and Technique Foundation of Henan Province,China(Grant No.SBGJ202001007)the National Natural Science Foundation of China(Grant Nos.31870809 and 32121001)the Special Fund for Young and Middle School Leaders of Henan Health Commission,China(Grant No.HNSWJW-2020017).
文摘Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)positively affect the initial control of non-small cell lung cancer(NSCLC).Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment.However,the mechanisms that control the resistance of EGFR-TKIs remain largely unknown.RNA structures have widespread and crucial functions in many biological regulations;however,the functions of RNA structures in regulating cancer drug resistance remain unclear.Here,the psoralen analysis of RNA interactions and structures(PARIS)method is used to establish the higher-order RNA structure maps of EGFRTKIs-resistant and-sensitive cells of NSCLC.Our results show that RNA structural regions are enriched in untranslated regions(UTRs)and correlate with translation efficiency(TE).Moreover,yrdC N6-threonylcarbamoyltransferase domain containing(YRDC)promotes resistance to EGFR-TKIs.RNA structure formation in YRDC 30 UTR suppresses embryonic lethal abnormal vision-like 1(ELAVL1)binding,leading to EGFR-TKI sensitivity by impairing YRDC translation.A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide(ASO)to perturb the interaction between RNA and protein.Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.
基金supported by the National Key R&D Program of China(Grant No.2021YFC0863300)the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB0490000)+6 种基金the CAMS Innovation Fund for Medical Sciences(Grant No.2021-I2M-1-024)the STI2030-Major Projects(Grant No.2021ZD0200900)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(Grant No.82221004)the National Natural Science Foundation of China(Grant Nos.32121001,32200460,and 32200460)the K.C.Wong Education Foundation(Grant No.GJTD-2019-08)the Shanghai Municipal Science and Technology Major Project,China(Grant No.2017SHZDZX01)the China National Postdoctoral Program for Innovative Talents(Grant No.BX2021291).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and global economic burden.The recurring global wave of infections has been exacerbated by growing variants of SARS-CoV-2.In this study,the virological characteristics of the original SARS-CoV-2 strain and its variants of concern(VOCs;including Alpha,Beta,and Delta)in vitro,as well as differential transcriptomic landscapes in multiple organs(lung,right ventricle,blood,cerebral cortex,and cerebellum)from the infected rhesus macaques,were elucidated.The original strain of SARS-CoV-2 caused a stronger innate immune response in host cells,and its VOCs markedly increased the levels of subgenomic RNAs,such as N,Orf9b,Orf6,and Orf7ab,which are known as the innate immune antagonists and the inhibitors of antiviral factors.Intriguingly,the original SARS-CoV-2 strain and Alpha variant induced larger alteration of RNA abundance in tissues of rhesus monkeys than Beta and Delta variants did.Moreover,a hyperinflammatory state and active immune response were shown in the right ventricles of rhesus monkeys by the up-regulation of inflammation-and immune-related RNAs.Furthermore,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected individuals.Collectively,these data provide insights into the pathogenesis of COVID-19 at the early stage of infection by the original SARS-CoV-2 strain and its VOCs.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.32121001 to YunGui Yang,92153303 to Ying Yang)CAS for Young Scientists in Basic Research Project(Grant No.YSBR-073 to Ying Yang)+3 种基金the Strategic Priority Research Program of CAS(Grant No.XDA16010501 to Yun-Gui Yang)the National Key R&D Program of China(Grant No.2018YFA0801200 to Ying Yang)the Youth Innovation Promotion Association of CAS(Grant No.Y2022040 to Ying Yang)the Beijing Nova Program,China(Grant Nos.Z201100006820104 and 20220484210 to Ying Yang).
文摘During mammalian preimplantation development,a totipotent zygote undergoes several cell cleavages and two rounds of cell fate determination,ultimately forming a mature blastocyst.Along with compaction,the establishment of apicobasal cell polarity breaks the symmetry of an embryo and guides subsequent cell fate choice.Although the lineage segregation of the inner cell mass(ICM)and trophectoderm(TE)is the first symbol of cell differentiation,several molecules have been shown to bias the early cell fate through their inter-cellular variations at much earlier stages,including the 2-and 4-cell stages.The underlying mechanisms of early cell fate determination have long been an important research topic.In this review,we summarize the molecular events that occur during early embryogenesis,as well as the current understanding of their regulatory roles in cell fate decisions.Moreover,as powerful tools for early embryogenesis research,single-cell omics techniques have been applied to both mouse and human preimplantation embryos and have contributed to the discovery of cell fate regulators.Here,we summarize their applications in the research of preimplantation embryos,and provide new insights and perspectives on cell fate regulation.
基金This study was funded by the Seed Funding,Army Medical University(Third Military Medical University),China(2016XYY04)Project from PLA(AWS17J014)The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘Background:Health care workers are at the frontline in the fight against infectious disease,and as a result are at a high risk of infection.During the 2014-2015 Ebola outbreak in West Africa,many health care workers contracted Ebola,some fatally.However,no members of the Chinese Anti-Ebola medical team,deployed to provide vital medical care in Liberia were infected.This study aims to understand how this zero infection rate was achieved.Methods:Data was collected through 15 in-depth interviews with participants from the People’s Liberation Army of China medical team which operated the Chinese Ebola Treatment Center from October 2014 to January 2015 in Liberia.Data were analysed using systematic framework analysis.Results:This study found numerous bio-psycho-socio-behavioural risk factors that directly or indirectly threatened the health of the medical team working in the Chinese Ebola Treatment Center.These factors included social and emotional stress caused by:(1)the disruption of family and social networks;(2)adapting to a different culture;(3)and anxiety over social and political unrest in Liberia.Exposure to Ebola from patients and local co-workers,and the incorrect use of personal protective equipment due to fatigue was another major risk factor.Other risk factors identified were:(1)shortage of supplies;(2)lack of trained health personnel;(3)exposure to contaminated food and water;(4)and long working hours.Comprehensive efforts were taken throughout the mission to mitigate these factors.Every measure was taken to prevent the medical team’s exposure to the Ebola virus,and to provide the medical team with safe,comfortable working and living environments.There were many challenges in maintaining the health safety of the team,such as the limited capability of the emergency command system(the standardized approach to the command,control,and coordination of an emergency response),and the lack of comprehensive international protocols for dealing with emerging infectious disease pandemics.Conclusions:The comprehe
文摘Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction （PCR） and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication （FLT3/ITD） and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 （19.7%） of 76 subjects, and NPM1 mutation in 20 （26.3%） subjects. Seven （9.2%） cases were positive for both FLT3/ITD and NPM1 mutations Significantly more FLT3/ITD aberration was detected in subjects with French-American-British （FAB） M1 （42.8%）. NPM1 mutation was frequently detected in subjects with M5 （47.1%） and infrequently in subjects with M2 （11.1%）. FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITD- positive group had a lower complete remission （CR） rate （53.3% vs. 83.6%）. Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival （OS） and relapse-free survival （RFS）. The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group （P=0.069）. Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.
基金Supported by The Scientific Research Foundation of the Ministry of Health,China,the Medical and Health Science Foundation,Zhejiang Province,China,No.WKJ-2009-2-021
文摘AIM:To study the diagnostic value of immunoglobulin heavy chain(IgH)and T-cell receptorγ (TCR-γ)gene monoclonal rearrangements in primary gastric lymphoma(PGL).METHODS:A total of 48 patients with suspected PGL at our hospital were prospectively enrolled in this study from January 2009 to December 2011.The patients were divided into three groups(a PGL group,a gastric linitis plastica group,and a benign gastric ulcer group)based on the pathological results(gastric mucosal specimens obtained by endoscopy or surgery)and follow-up.Endoscopic ultrasonography(EUS)and EUSguided biopsy were performed in all the patients.The tissue specimens were used for histopathological examination and for IgH and TCR-γ gene rearrangement polymerase chain reaction analyses.RESULTS:EUS and EUS-guided biopsy were successfully performed in all 48 patients.In the PGL group(n=21),monoclonal IgH gene rearrangements were detected in 14(66.7%)patients.A positive result for each set of primers was found in 12(57.1%),8(38.1%),and 4(19.0%)cases using FR1/JH,FR2/JH,and FR3/JH primers,respectively.Overall,12(75%)patients with mucosal-associated lymphoid tissue lymphoma(n=16)and 2(40%)patients with diffuse large B-cell lymphoma(n=5)were positive for monoclonal IgH gene rearrangements.No patients in the gastric linitis plastica group(n=17)and only one(10%)patient in the benign gastric ulcer group(n=10)were positive for a monoclonal IgH gene rearrangement.No TCRgene monoclonal rearrangements were detected.The sensitivity of monoclonal IgH gene rearrangements was 66.7%for a PGL diagnosis,and the specificity was96.4%.In the PGL group,8(100%)patients with stage IIE PGL(n=8)and 6(46.1%)patients with stage IE PGL(n=13)were positive for monoclonal IgH gene rearrangements.CONCLUSION:IgH gene rearrangements may be associated with PGL staging and may be useful for the diagnosis of PGL and for differentiating between PGL and gastric linitis plastica.
