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First progeria monkey model generated using base editor

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Protein & Cell 2020年第12期11卷 862-865页

作者： Pradeep Reddy Yanjiao Shao Reyna Hernandez-Benitez Estrella Nunez Delicado Juan Carlos Izpisua Belmonte Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA Universidad Catolica San Antonio de Murcia(UCAM) Campus de los JerdnimosN°13512Guadalupe 30107Spain

In this issue,Wang et al.report on the generation of a nonhuman primate model of Hutchinson-Gilford progeria syndrome(HGPS)using a base editor.Base editing is an emerging novel genome editing technique for modifying a single base pair at specific sites in the genome.Base editors(BEs)have two prin cipal comp orients,a catalytically in active or single strand cleaving Cas-variant,which binds to the guide RNA and a nucleobase deaminase domain to convert specific base pairs at the target loci(Komor et al.,2016;Nishida et al.,2016;Gaudelli et al.,2017).Cytosine base editor(CBE)and adenine base editor(ABE)are two baseeditors,which con vert Cytosi ne-Gua nine(C-G)to Thymine-Adenine(T-A)and A-T to G-C,respectively.

关键词： base convert editor

Control of rice ratooning ability by a nucleoredoxin that inhibits histidine kinase dimerization to attenuate cytokinin signaling in axillary buds

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Molecular Plant 2023年第12期16卷 1911-1926页

作者： Yilong Yao Denghao Xiang Nai Wu Yao Wang Yu Chen Yang Yuan Ying Ye Dan Hu Chang Zheng Yu Yan Qingya Lv Xiaokai Li Guoxing Chen Honghong Hu Haiyan Xiong Shaobing Peng Lizhong Xiong National Key laboratory of Crop genetic Improvement Hubei Hongshan Laboratoryand National Center of Plant Gene Research(Wuhan)Huazhong Agricultural UniversityWuhan430070China

Rice ratooning,the fast outgrowth of dormant buds on stubble,is an important cropping practice in rice production.However,the low ratooning ability(RA)of most rice varieties restricts the application of this cost-efficient system,and the genetic basis of RA remains unknown.In this study,we dissected the genetic architecture of RA by a genome-wide association study in a natural rice population.Rice ratooning ability 3(RRA3),encoding a hitherto not characterized nucleoredoxin involved in reduction of disulfide bonds,was identified as the causal gene of a major locus controlling RA.Overexpression of RRA3 in rice significantly accelerated leaf senescence and reduced RA,whereas knockout of RRA3 significantly delayed leaf senescence and increased RA and ratoon yield.We demonstrated that RRA3 interacts with Oryza sativa histidine kinase 4(OHK4),a cytokinin receptor,and inhibits the dimerization of OHK4 through disulfide bond reduction.This inhibition ultimately led to decreased cytokinin signaling and reduced RA.In addition,variations in the RRA3 promoter were identified to be associated with RA.Introgression of a superior haplotype with weak expression of RRA3 into the elite rice variety Guichao 2 significantly increased RA and ratoon yield by 23.8%.Collectively,this study not only uncovers an undocumented regulatory mechanism of cytokinin signaling through de-dimerization of a histidine kinase receptor-but also provides an eximious gene with promising value for ratoon rice breeding.

关键词： ratoon rice ratooning ability redox histidine kinase cytokinin signaling

Genome-wide binding analysis of transcription factor Rice Indeterminate 1 reveals a complex network controlling rice floral transition

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Journal of Integrative Plant Biology 2022年第9期64卷 1690-1705页

作者： Shuo Zhang Li Deng Lun Zhao Changyin Wu National Key laboratory of Crop genetic Improvement and National Center of Plant gene Research(Wuhan) Hubei Hongshan LaboratoryHuazhong Agricultural UniversityWuhan430070 China

RICE INDETERMINATE 1(RID1)plays a critical role in controlling floral transition in rice(Oryza sativa).However,the molecular basis for this effect,particularly the target genes and regulatory specificity,remains largely unclear.Here,we performed chromatin immunoprecipitation followed by sequencing(ChIP-seq)in young leaves at the pre-floral-transition stage to identify the target genes of RID1,identifying 2,680 genes associated with RID1 binding sites genome-wide.RID1 binding peaks were highly enriched for TTTGTC,the direct binding motif of the INDETERMINATE DOMAIN protein family that includes RID1.Interestingly,CACGTG and GTGGGCCC,two previously uncharacterized indirect binding motifs,were enriched through the interactions of RID1 with the novel floweringpromoting proteins OsPIL12 and OsTCP11,respectively.Moreover,the ChIP-seq data demonstrated that RID1 bound to numerous rice heading-date genes,such as HEADING DATE1(HD1)and FLAVIN-BINDING,KELCH REPEAT,F-BOX 1(OsFKF1).Notably,transcriptome sequencing(RNA-seq)analysis revealed roles of RID1 in diverse developmental pathways.genetic analysis combined with genome-wide ChIP-seq and RNA-seq results showed that RID1 directly binds to the promoter of OsERF#136(a repressor of rice flowering)and negatively regulates its expression.Overall,our findings provide new insights into the molecular and genetic mechanisms underlying rice floral transition and characterize OsERF#136 as a previously unrecognized direct target of RID1.

关键词： ChIP-seq floral transition OsERF#136 rice(Oryza sativa) RID1 RNA-seq

miR395-regulated sulfate metabolism exploits pathogen sensitivity to sulfate to boost immunity in rice

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Molecular Plant 2022年第4期15卷 671-688页

作者： Zeyu Yang Shugang Hui Yan Lv Miaojing Zhang Dan Chen Jingjing Tian Haitao Zhang Hongbo Liu Jianbo Cao Wenya Xie Changyin Wu Shiping Wang Meng Yuan National Key laboratory of Crop genetic Improvement National Center of Plant Gene Research(Wuhan)Hubei Hongshan LaboratoryHuazhong Agricultural UniversityWuhan 430070China

MicroRNAs (miRNAs) play important roles in plant physiological activities. However, their roles and molecular mechanisms in boosting plant immunity, especially through the modulation of macronutrient metabolism in response to pathogens, are largely unknown. Here, we report that an evolutionarily conserved miRNA, miR395, promotes resistance to Xanthomonas oryzae pv. oryzae (Xoo) and X. oryzae pv. oryzicola (Xoc), two destructive bacterial pathogens, by regulating sulfate accumulation and distribution in rice. Specifically, miR395 targets and suppresses the expression of the ATP sulfurylase gene OsAPS1, which functions in sulfate assimilation, and two sulfate transporter genes, OsSULTR2;1 and OsSULTR2;2, which function in sulfate translocation, to promote sulfate accumulation, resulting in broad-spectrum resistance to bacterial pathogens in miR395-overexpressing plants. genetic analysis revealed that miR395-triggered resistance is involved in both pathogen-associated molecular pattern-triggered immunity and R gene-mediated resistance. Moreover, we found that accumulated sulfate but not S-metabolites inhibits proliferation of pathogenic bacteria, revealing a sulfate-mediated antibacterial defense mechanism that differs from sulfur-induced resistance. Furthermore, compared with other bacteria, Xoo and Xoc, which lack the sulfate transporter CysZ, are sensitive to high levels of extracellular sulfate. Accordingly, miR395-regulated sulfate accumulation impaired the virulence of Xoo and Xoc by decreasing extracellular polysaccharide production and biofilm formation. Taken together, these results suggest that rice miR395 modulates sulfate metabolism to exploit pathogen sensitivity to sulfate and thereby promotes broad-spectrum resistance.

关键词： miR395 sulfate metabolism disease resistance CysZ rice

The labyrinth of nuclear reprogramming

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分子细胞生物学报:英文版 2011年第6期3卷 327-329页

作者： Ignacio Sancho-Martinez Emmanuel Nivet Juan Carlos Izpisua Belmonte Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA Center for Regenerative Medicine in Barcelona Dr Aiguader 88Barcelona 08003Spain

Human embryonic stem cells(ESCs)have the capability to differentiate into all somatic cell types,a process that recapitu-lates the early stages of human develop-ment.However,the use of ESCs raises several controversies,particularly concern-ing the ethical dilemma regarding the use of human embryonic material and the need for embryo destruction.The discov-ery of induced pluripotent stem cell(iPSC)technology in 2006(Takahashi and Yamanaka,2006)opened the door for possible application of pluripotent stem-cell-related therapies in the clinic as well as for the generation of patient-derived pluripotent stem cells suitable for disease modeling in vitro.

关键词： programming destruction opened

TERC suppresses PD-L1 expression by downregulating RNA binding protein HuR

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Science China(Life Sciences) 2022年第12期65卷 2505-2516页

作者： Heping Jin Yanlian Chen Jian Ren Junjiu Huang Yong Zhao Haiying Liu MOE Key laboratory of gene Function and Regulation School of Life SciencesSun Yat-sen UniversityGuangzhou 510006China

TERC is the RNA component of telomerase,and provides a template for TERT to synthesize telomere repeats at chromosome ends.Increasing evidence has revealed that TERC is involved in other biological processes beyond telomerase.Here,we found that the expression level of TERC is negatively correlated with PD-L1 and that ectopic expression of TERC but not TERT in ALT cells significantly inhibits PD-L1,suggesting that TERC suppresses PD-L1 expression in a telomerase-independent manner.Mechanistically,instead of regulating PD-L1 m RNA directly,TERC accelerates PD-L1 m RNA degradation by inhibiting the expression of Hu R,which binds to the 3′UTR of PD-L1 m RNA and maintains its stability.We also found that the small molecule AS1842856,a Fox O1 inhibitor,promotes TERC expression and reverses the PD-L1 upregulation caused by chemotherapy,providing a potential combination cancer therapy that avoids cancer immune escape during chemotherapy.

关键词： TERC PD-L1 HuR FoxO1 inhibitor

Hot spots of DNA double-strand breaks and genomic contacts of human rDNA units are involved in epigenetic regulation

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分子细胞生物学报:英文版 2015年第4期7卷 366-382页

作者： Nickolai A.Tchurikov Daria M.Fedoseeva Dmitri V.Sosin Anastasia V.Snezhkina Nataliya V.Melnikova Anna V.Kudryavtseva Yuri V.Kravatsky Olga V.Kretova Department of Epigenetic Mechanisms of gene expression Regulation Engelhardt Institute of Molecular BiologyMoscow 119334Russia Group of Postgenomic Studies Engelhardt Institute of Molecular BiologyMoscow 119334Russia laboratory of DNA-Protein Interactions Engelhardt Institute of Molecular BiologyMoscow 119334Russia

DNA double-strand breaks(DSBs)are involved in many cellular mechanisms,including replication,transcription,and genome rearrangements.The recent observation that hot spots of DSBs in human chromosomes delimit DNA domains that possess coordinately expressed genes suggests a strong relationship between the organization of transcription patterns and hot spots of DSBs.In this study,we performed mapping of hot spots of DSBs in a human 43-kb ribosomal DNA(rDNA)repeated unit.We observed that rDNA units corresponded to the most fragile sites in human chromosomes and that these units possessed at least nine specific regions containing clusters of extremely frequently occurring DSBs,which were located exclusively in non-coding intergenic spacer(IGS)regions.The hot spots of DSBs corresponded to only a specific subset of DNase-hypersensitive sites,and coincided with CTCF,PARP1,and HNRNPA2B1 binding sites,and H3K4me3 marks.Our rDNA-4C data indicate that the regions of IGS containing the hot spots of DSBs often form contacts with specific regions in different chromosomes,including the pericentromeric regions,as well as regions that are characterized by H3K27ac and H3K4me3 marks,CTCF binding sites,ChIA-PET and RIP signals,and high levels of DSBs.The data suggest a strong link between chromosome breakage and several different mechanisms of epigenetic regulation of gene expression.

关键词： double-strand breaks fragile sites rDNA IGS PARP1 HNRNPA2B1 4C

The C-Terminal Hypervariable Domain Targets Arabidopsis ROP9 to the Invaginated Pollen Tube Plasma Membrane

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Molecular Plant 2013年第4期6卷 1362-1364页

作者： Sha Li[a],, Liang-Zi Zhou[a],, Qiang-Nan Feng[a], Sheila McCormick[b] Yan Zhang[a],[b], [a] State Key laboratory of Crop Biology College of Life Sciences Shandong Agricultural University Tai’an 271018 China[b] Plant Gene Expression Center United States Department of Agriculture and University of California Berkeley CA 94710 USA

Dear Editor, The small GTPase ROPs are molecular switches in diverse developmental and cellular processes in plants （Yang, 2002）. Based on their genomic organization, ROPs have been classified into two subgroups （Winge et al., 2000）. Type I ROPs reg- ulate the dynamic organization of the actin cytoskeleton, a tip-focused Ca2＋-gradient, and the production of reactive oxy- gen species, thus playing essential roles in pollen tube growth presumably by integrating input signals into diverse output cellular activities （Nibau et al., 2006）. The GTP-bound, active form of type I ROPs localize at the apical plasma membrane of pollen tubes to direct polar growth, while their GDP-bound, inactive forms are cytoplasmic （Yang, 2002）. Localization of type I ROPs at the apical plasma membrane of pollen tubes is dynamically regulated by coordinated activities of their upstream regulators including guanine nucleotide exchange factors （RopGEFs）, GTPase activating proteins （RopGAPs）, and guanine nucleotide dissociation inhibitors （RhoGDIs）（Hwang et al., 2010）.

关键词： ARABIDOPSIS POLLEN tube CELL membranes C-terminal binding proteins PLANT reproduction

Association of TNFA(-308G/A),IFNG(+874 A/T)and IL-10(-819 C/T)polymorphisms with protection and susceptibility to dengue in Brazilian population

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Asian Pacific Journal of Tropical Medicine 2017年第11期10卷 1065-1071页

作者： Ana Caroline Melo dos Santos Edilson Leite de Moura Jean Moises Ferreira Alexandre Wendell Araujo de Moura Ailson Darlan Sales Ferreira Rubens Pereira Bezerra Diego de Siqueira Figueiredo Karol Fireman de Farias Tiago Gomes de Andrade Elaine Virginia Martins de Souza Figueiredo Molecular Biology and Gene Expression Laboratory Federal University of AlagoasCampus ArapiracaAv Manoel Severino BarbosaBom SucessoArapiracaAL57309-005Brazil Faculty of Medicine Federal University of AlagoasCampus AC SimoesTabuleiro dos MartinsMaceioAlagoasBrazil

Objective: To evaluate gene polymorphisms and their association with susceptibility to dengue.Methods: A retrospective case-control study was performed with 262 subjects,comprising 78 dengue fever(DF) patients, 49 dengue hemorrhagic fever(DHF) patients and 135 healthy controls. Genotypic and allelic profiles were identified using polymerase chain reaction based in real time and amplification-refractory mutation system.Results: We observed a protective association of IL-10(-819 C/T) C allele(P = 0.028,OR = 0.56, CI = 0.34–0.91) against DHF, while the C/T(P = 0.047, OR = 2.10,CI = 1.01–4.38) and T/T(P = 0.008, OR = 3.82, CI = 1.38–10.59) genotypes were associated with DHF and DF, respectively. The dominant model TNFA-308 GA + AA(P = 0.043, OR = 0.45, CI = 0.20–1.00) genotypes were found to have protective effect against dengue infection. A protective association among the IFNG(+874 A/T) A/T genotype against DF(P = 0.02, OR = 0.46, CI = 0.24–0.89) and DHF(P = 0.034,OR = 0.43, CI = 0.19–0.95) was observed. When the studied single-nucleotide polymorphism was analyzed in combination, the combination GTA(P = 0.022, OR = 2.95,CI = 1.18–7.41) was statistically significantly associated with susceptibility to DF and the combination GCT(P = 0.035, OR = 0.28, CI = 0.08–0.90) with protection against the development of DHF.Conclusions: This research identifies the association of the IFNG(+874 A/T), TNFA(-308 G/A), IL-10(-819 C/T) genotypes as a factor for protection, susceptibility and severity to dengue.

关键词： Immune system IFNG TNFA IL-10 Dengue Polymorphism