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The rapid proximity labeling system PhastID identifies ATP6AP1 as an unconventional GEF for Rheb

细胞研究（英文版） 2024年第5期34卷 355-369页

作者： Ran Feng Feng Liu Ruofei Li Zhifen Zhou Zhuoheng Lin Song Lin Shengcheng Deng Yingying Li Baoting Nong Ying Xia Zhiyi Li Xiaoqin Zhong Shuhan Yang Gang Wan Wenbin Ma Su Wu Zhou Songyang MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolGuangzhou Key Laboratory of Healthy Aging ResearchSchool of Life SciencesInstitute of Healthy Aging ResearchSun Yat-sen UniversityGuangzhouGuangdongChina Sun Yat-sen Memorial Hospital Sun Yat-sen UniversityGuangzhouGuangdongChina MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolGuangzhou Key Laboratory of Healthy Aging ResearchSchool of Life SciencesInstitute of Healthy Aging ResearchSun Yat-sen UniversityGuangzhouGuangdongChina Sun Yat-sen Memorial Hospital Sun Yat-sen UniversityGuangzhouGuangdongChina

Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1(mTORC1)to coordinate signaling cascades in response to nutrients and growth *** extensive studies,the guanine nucleotide exchange factor(GEF)that directly activates Rheb remains unclear,at least in part due to the dynamic and transient nature of protein-protein interactions(PPIs)that are the hallmarks of signal ***,we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase(PhBPL)-assisted biotin identification(PhastID)and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using *** particular,we found that the lysosomal V-ATPase subunit ATP6AP1 could dynamically interact with ***6AP1 could directly bind to Rheb through its last 12 amino acids and utilizes a tri-aspartate motif in its highly conserved C-tail to enhance Rheb GTP *** fact,targeting the ATP6AP1 C-tail could block Rheb activation and inhibit cancer cell proliferation and *** findings highlight the versatility of PhastID in mapping transient PPIs in live cells,reveal ATP6AP1's role as an unconventional GEF for Rheb,and underscore the importance of ATP6AP1 in integrating mTORC1 activation signals through Rheb,filling in the missing link in Rheb/mTORC1 activation.

关键词： rapid system rheb identifies labeling phastid proximity unconventional

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CRISPR-assisted transcription activation by phaseseparation proteins

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Protein & Cell 2023年第12期14卷 874-887页

作者： Jiaqi Liu Yuxi Chen Baoting Nong Xiao Luo Kaixin Cui Zhan Li Pengfei Zhang Wenqiong Tan Yue Yang Wenbin Ma Puping Liang Zhou Songyang State Key Laboratory of Biocontrol MOE Key Laboratory of Gene Function and Regulation and Guangzhou Key Laboratory of Healthy Aging ResearchSchool of Life SciencesSun Yat-senUniversityGuangzhou510275China Sun Yat-sen Memorial Hospital Sun Yat-sen UniversityGuangzhou 510275China Lumiere Therapeutics Suzhou215000China

The clustered regularly interspaced short palindromic repeats(CRISPR)-Cas9 system has been widely used for genome engineering and transcriptional regulation in many different *** CRISPR-activation(CRISPRa)platforms often require multiple components because of inefficient transcriptional ***,we fused different phase-separation proteins to dCas9-VPR(dCas9-VP64-P65-RTA)and observed robust increases in transcriptional activation ***,human NUP98(nucleoporin 98)and FUS(fused in sarcoma)IDR domains were best at enhancing dCas9-VPR activity,with dCas9-VPR-FUS IDR(VPRF)outperforming the other CRISPRa systems tested in this study in both activation efficiency and system ***9-VPRF overcomes the target strand bias and widens gRNA designing windows without affecting the off-target effect of *** findings demonstrate the feasibility of using phase-separation proteins to assist in the regulation of gene expression and support the broad appeal of the dCas9-VPRF system in basic and clinical applications.

关键词： CRISPR transcriptional activation phase-separation proteins

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Single-base resolution mapping of 2′-O-methylation sites by an exoribonuclease-enriched chemical method

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Science China(Life Sciences) 2023年第4期66卷 800-818页

作者： Ping Zhang Junhong Huang Wujian Zheng Lifan Chen Shurong Liu Anrui Liu Jiayi Ye Jie Zhou Zhirong Chen Qiaojuan Huang Shun Liu Keren Zhou Lianghu Qu Bin Li Jianhua Yang MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolSchool of Life SciencesThe Fifth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510275China Department of Chemistry The University of ChicagoChicagoIL 60637USA Department of Systems Biology Beckman Research Institute of City of HopeMonroviaCA 91016USA

2′-O-methylation(Nm)is one of the most abundant RNA epigenetic modifications and plays a vital role in the post-transcriptional regulation of gene *** Nm mapping approaches are normally limited to highly abundant RNAs and have significant technical hurdles in m RNAs or relatively rare non-coding RNAs(nc RNAs).Here,we developed a new method for enriching Nm sites by using RNA exoribonuclease and periodate oxidation reactivity to eliminate 2′-hydroxylated(2′-OH)nucleosides,coupled with sequencing(Nm-REP-seq).We revealed several novel classes of Nm-containing nc RNAs as well as m RNAs in humans,mice,and *** found that some novel Nm sites are present at fixed positions in different t RNAs and are potential substrates of fibrillarin(FBL)methyltransferase mediated by sno ***,we discovered,for the first time,that Nm located at the 3′-end of various types of nc RNAs and fragments derived from *** approach precisely redefines the genome-wide distribution of Nm and provides new technologies for functional studies of Nm-mediated gene regulation.

关键词： 2′-O-methylation MgR exoribonuclease periodate oxidation epitranscriptome transcriptome

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Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma

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Cellular & Molecular Immunology 2024年第10期21卷 1120-1130页

作者： Yongchun Wang Weibai Chen Shuang Qiao Hao Zou Xing-juan Yu Yanyan Yang Zhixiong Li Junfeng Wang Min-shan Chen Jing Xu Limin Zheng Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou510060PR China Key Laboratory of Gene Function and Regulation of the Ministry of Education School of Life SciencesSun Yat-sen UniversityGuangzhou510275PR China Department of Liver Surgery Sun Yat-sen University Cancer CenterGuangzhouPR China

Metabolic changes play a crucial role in determining the status and function of macrophages,but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully ***,we investigated the phenotype,contribution,and regulatory mechanisms of lipid droplet(LD)-laden macrophages(LLMs)in hepatocellular carcinoma(HCC).Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC *** LLMs displayed immunosuppressive phenotypes(with extensive expression of TREM2,PD-L1,CD206,and CD163)and attenuated the antitumor activities of CD8^(+)T ***,tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in *** prolong LLM survival and promote CCL20 secretion,which further recruits CCR6^(+)Tregs to HCC *** LLM formation by targeting DGAT1 and DGAT2,which catalyze the synthesis of triglycerides,significantly reduced Treg recruitment,and delayed tumor growth in a mouse hepatic tumor *** results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.

关键词： Lipid droplets Macrophage survival CCL20 Treg Hepatocellular carcinoma

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RNA Modifications and Epitranscriptomics

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Genomics, Proteomics & Bioinformatics 2023年第4期21卷 675-677页

作者： Chengqi Yi Jianhua Yang State Key Laboratory of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeijing 100871China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100871China Department of Chemical Biology and Synthetic and Functional Biomolecules Center College of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China The Fifth Affiliated Hospital Sun Yat-sen UniversityZhuhai 519000China

More than 170 distinct chemical modifications have been identified in non-coding and coding *** evidence suggests that RNA modifications play pivotal roles at both the molecular and physiological *** of RNAmodifying enzymes has been linked to various human cancers and developmental *** expanding understanding of RNA modifications in molecular and cellular functions further suggests promising prospects for therapeutic ***,the creation of effective mRNA vaccines against coronavirus disease 2019(COVID-19),based on RNA base modification,was honored with the Nobel Prize in Physiology or Medicine 2023(https://***/prizes/medicine/2023/press-release/).Aiming to provide a forum for emerging advances in detection and functional studies of epitranscriptomic modifications,we have organized a special issue"RNA Modifications and Epitranscriptomics"for the journal Genomics,Proteomics&Bioinformatics(GPB).This special issue encompasses a wide range of topics,including:(1)dynamic landscapes of RNA modifications in various organisms,including animals,plants,and viruses;(2)mechanistic regulation of m^(6)A and m5 C modifications in human diseases and plant responses to stresses;(3)an online platform for unveiling the context-specific m^(6)A methylation and m^(6)Aaffecting mutation;and(4)the regulatory role of non-coding RNAs(ncRNAs),including tRNAs and circular RNAs(circRNAs),in gene expression regulation.

关键词： journal landscape modification

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Protocol for capturing genome-wide chromatin interactions in Arabidopsis

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STAR Protocols 2025年第2期6卷 103702页

作者： Shu, Jiayue Xiao, Suxin Wang, Dingyue Yang, Minqi Zhou, Yue State Key Laboratory of Gene Function and Modulation Research School of Advanced Agricultural Sciences Peking-Tsinghua Center for Life Sciences Peking University Beijing 100871 China

High-order chromatin structure is essential for the regulation of plant growth and development. Here, we present a protocol for capturing genome-wide chromatin interactions in Arabidopsis. We describe steps for tissue fixation, nuclei isolation, chromatin digestion, ligation, sonication, and library preparation. This protocol has potential application in 3D chromatin analysis in many species of plants. For complete details on the use and execution of this protocol, please refer to Shu et al.,¹ Yin et al.,² and Yang et al.^3,4 © 2025 The Author(s)

关键词： genetics Plant sciences Sequencing

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Pancreatic agenesis and altered m6A methylation in the pancreas of PDX1-mutant cynomolgus macaques

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Zoological research 2024年第6期45卷 1188-1200页

作者： Wen-Hui Zhang Jiong-Han Zhuang Yun-Yi Guo Xue-Ying Chen Ya-Qing Li Jie-Qiu Xu An-Ran Zhang Bao-Yi Chen Wei Meng Yan-Hua Zhu Jun-Jiu Huang Yong-Long Guo Shi-Hua Yang College of Veterinary Medicine South China Agricultural UniversityGuangzhouGuangdong 510642China College of Coastal Agricultural Sciences Guangdong Ocean UniversityZhanjiangGuangdong 524088China Key Laboratory of Reproductive Medicine of Guangdong Province School of Life Sciences and First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510275China MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Department of Endocrinology and Metabolism Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong510630China Guangdong Provincial Key Laboratory of Diabetology Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China

As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell *** in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal diabetes ***,the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal *** this study,three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology,all of which succumbed shortly postpartum,exhibiting pancreatic ***,one tri-allelic PDX1-mutant cynomolgus macaque(designated as M4)developed a pancreas,whereas the two monoallelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic *** sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions,indicating developmental delay and PDX1haploinsufficiency.A marked change in m6A methylation was identified in the M4 pancreas,confirmed through cultured ***,overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet *** study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.

关键词： PDX1 MODY4 Cynomolgus macaques M6A methylation modification

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Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1730-1744页

作者： Zhenzhen Fang Gang Shen Yina Wang Fuyan Hong Xiumei Tang Yongcheng Zeng Ting Zhang Huanyi Liu Yanmei Li Jinhong Wang Jing Zhang Anton Gao Weiwei Qi Xia Yang Ti Zhou Guoquan Gao Department of Biochemistry Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhou 510080China Department of VIP Medical Center the Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510080China Physical Examination Center the Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510080China Department of Clinical Laboratory Guangzhou First People's HospitalGuangzhou 510080China Guangdong Key Laboratory of Liver Disease Research the Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 51008China Department of Health Sciences College of Health SolutionsArizona State UniversityTempeUSA Guangdong Engineering&Technology Research Center for Gene Manipulation and Biomacromolecular Products Sun Yat-Sen UniversityGuangzhou 510080China Guangdong Province Key Laboratory of Diabetology Guangzhou 510o80China Guangdong Province Key Laboratory of Brain Function and Disease Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhou 510080China

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide,and the development of nonalcoholic steatohepatitis(NASH)might cause irreversible hepatic ***(HLP)is the leading risk factor for *** study aims to illuminate the causative contributor and potential mechanism of Kallistatin(KAL)mediating HLP to NAFLD.221 healthy control and 253 HLP subjects,62 healthy control and 44 NAFLD subjects were *** plasma KAL was significantly elevated in HLP subjects,especially in hypertriglyceridemia(HTG)subjects,and positively correlated with liver ***,KAL levels of NAFLD patients were significantly *** transgenic mice induced hepatic steatosis,inflammation,and fibrosis with time and accelerated inflammation development in high-fat diet(HFD)*** contrast,KAL knockout ameliorated steatosis and inflammation in high-fructose diet(HFruD)and methionine and choline-deficient(MCD)diet-induced NAFLD ***,KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase(ATGL)and comparative gene identification 58(CGl-58)by LRP6/Gas/PKA/GSK3βpathway through down-regulating peroxisome proliferator-activated receptor(PPARy)and up-regulating kruppel-like factor four(KLF4),***-58 is bound to NF-kB p65 in the cytoplasm,and diminishing CGl-58 facilitated p65 nuclear translocation and TNFa ***,hepatic CGl-58-overexpress reverses NASH in KAL transgenic ***,free fatty acids up-regulated KAL against thyroid hormone in ***,Fenofibrate,one triglyceride-lowering drug,could reverse hepatic steatosis by down-regulating *** results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.

关键词： GSK3β inflammation elevated

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The functional analysis of transiently upregulated miR-101 suggests a “braking” regulatory mechanism during myogenesis

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Science China(Life Sciences) 2021年第10期64卷 1612-1623页

作者： Shurong Liu Shujuan Xie Huafeng Chen Bin Li Zhirong Chen Yeya Tan Jianhua Yang Lingling Zheng Zhendong Xiao Qi Zhang Lianghu Qu MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Vaccine Research Institute of Sun Yat-sen University the Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China Cell-Gene Therapy Translational Medicine Research Center the Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China

Skeletal muscle differentiation is a highly coordinated process that involves many cellular signaling pathways and microRNAs(miRNAs).A group of muscle-specific miRNAs has been reported to promote myogenesis by suppressing key signaling pathways for cell ***,the functional role and regulatory mechanism of most non-muscle-specific miRNAs with stage-specific changes during differentiation are largely ***,we describe the functional characterization of miR-101a/b,a pair of non-muscle-specific miRNAs that show the largest change among a group of transiently upregulated miRNAs during myogenesis in C2C12 *** overexpression of miR-101a/b inhibits myoblast differentiation by suppressing the p38/MAPK,Interferon Gamma,and Wnt pathways and enhancing the C/EBP ***2a,a key protein in the p38/MAPK pathway,was identified as a direct target of miR-101a/***,we found that the long non-coding RNA(lncRNA)Malat1,which promotes muscle differentiation,interacts with miR-101a/b,and this interaction competes with Mef2a mRNA to relieve the inhibition of the p38/MAPK pathway during *** results uncovered a“braking”role in differentiation of transiently upregulated miRNAs and provided new insights into the competing endogenous RNA(ceRNA)regulatory mechanism in myoblast differentiation and myogenesis.

关键词： miR-101a/b p38/MAPK signaling pathway Mef2a Malat1 skeletal muscle differentiation

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A two-step self-pollination mechanism maximizes fertility in Brassicaceae

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Cell 2025年第11期188卷 2845-2855.e8页

作者： Liu, Pu Quan, Xin Song, Zihan Li, Wenhao Wang, Yuan Gu, Hongya Xie, Daoxin Yang, Weicai Dresselhaus, Thomas Zhong, Sheng Qu, Li-Jia State Key Laboratory for Gene Function and Modulation Research Peking-Tsinghua Center for Life Sciences New Cornerstone Science Laboratory College of Life Sciences Peking University Beijing 100871 China Ministry of Education Key Laboratory of Bioinformatics Tsinghua-Peking Center for Life Sciences and School of Life Sciences Tsinghua University Beijing 100084 China Yazhouwan National Laboratory 8 Huanjing Road Yacheng Hainan Sanya 572025 China Cell Biology and Plant Biochemistry University of Regensburg Regensburg 93053 Germany

Self-pollination in self-compatible plant species often occurs prior to flower opening. By tracking the temporal progress of pollination in Arabidopsis, we observed that pollen predominantly targets the lateral region of the stigma in unopened flowers. Notably, approximately 7 h after flower opening, flowers close, thereby pressing anthers toward the central region of the stigma for a second self-pollination. This two-step self-pollination results in a doubling of pollen deposition, which significantly increases the ovule-targeting ratio and improves fertility under pollen-limiting conditions, as evident in the anther-dehiscence-defective mutant myb108 and under environmental stress conditions. Analysis using gamete-interaction-defective mutants hap2/gcs1 and dmp8 dmp9 revealed that the timely separation of both pollination events promotes fertilization recovery efficiency. A similar two-step pollination was observed in two other self-pollinating but not in outcrossing Brassicaceae species. This mechanism represents a reproductive assurance strategy in predominantly self-pollinating annuals to maximize fertility under unfavorable conditions. © 2025 The Author(s)

关键词： Arabidopsis Brassicaceae fertility fertilization recovery heat stress pollination reproduction stigma

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