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Phosphorylation of ATF2 promotes odontoblastic differentiation via intrinsic HAT activity

Journal of Genetics and Genomics 2023年第7期50卷 497-510页

作者： Huanyan Zuo Yao Xiao Jiahao Han Yuxiu Lin Cheng Tian Shu Zhang Guohua Yuan Huan Liu Zhi Chen State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of EducationHubei Key Laboratory of StomatologySchool&Hospital of StomatologyWuhan UniversityWuhanHubei 430079China Department of Cariology and Endodontics School of StomatologyWuhan UniversityWuhanHubei 430079China Department of Periodontology School of StomatologyWuhan UniversityWuhanHubei 430079China TaiKang Center for Life and Medical Sciences Wuhan UniversityWuhanHubei 430079China

Mouse dental papilla cells(mDPCs)are cranial neural crest-derived dental mesenchymal cells that give rise to dentin-secreting odontoblasts after the bell stage during odontogenesis.The odontoblastic differentiation of mDPCs is spatiotemporally regulated by Transcription factors(TFs).Our previous work reveals that chromatin accessibility was correlated with the occupation of the basic leucine zipper TF family during odontoblastic differentiation.However,the detailed mechanism by which TFs regulate the initiation of odontoblastic differentiation remains elusive.Here,we report that phosphorylation of ATF2(p-ATF2)is particularly increased during odontoblastic differentiation in vivo and in vitro.ATAC-seq and p-ATF2 CUT&Tag experiments further demonstrate a high correlation between p-ATF2 localization and increased chromatin accessibility of regions near mineralization-related genes.Knockdown of Atf2 inhibits the odontoblastic differentiation of mDPCs,while overexpression of p-ATF2 promotes odontoblastic differentiation.ATAC-seq after overexpression of p-ATF2 reveals that p-ATF2 increases the chromatin accessibility of regions adjacent to genes associated with matrix mineralization.Furthermore,we find that p-ATF2 physically interacts with and promotes H2BK12 acetylation.Taken together,our findings reveal a mechanism that p-ATF2 promotes odontoblastic differentiation at initiation via remodeling chromatin accessibility and emphasize the role of the phosphoswitch model of TFs in cell fate transitions.

关键词： Odontoblast Dental papilla Mesenchymal stem cells ATF Transcription factors Cell differentiation Chromatin accessibility

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Asymmetric cell division in plant development

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Journal of Integrative Plant Biology 2023年第2期65卷 343-370页

作者： Yi Zhang Tongda Xu Juan Dong Plant Synthetic Biology Center Haixia Institute of Science and Technologyand College of Life SciencesFujian Agriculture and Forestry UniversityFuzhou 350002 China The Waksman Institute of Microbiology Rutgersthe State University of New JerseyPiscatawayNJ 08854USA Department of Plant Biology Rutgersthe State University of New JerseyNew BrunswickNJ 08891USA

Asymmetric cell division(ACD) is a fundamental process that generates new cell types during development in eukaryotic species.In plant development,post-embryonic organogenesis driven by ACD is universal and more important than in animals,in which organ pattern is preset during embryogenesis.Thus,plant development provides a powerful system to study molecular mechanisms underlying ACD.During the past decade,tremendous progress has been made in our understanding of the key components and mechanisms involved in this important process in plants.Here,we present an overview of how ACD is determined and regulated in multiple biological processes in plant development and compare their conservation and specificity among different model cell systems.We also summarize the molecular roles and mechanisms of the phytohormones in the regulation of plant ACD.Finally,we conclude with the overarching paradigms and principles that govern plant ACD and consider how new technologies can be exploited to fill the knowledge gaps and make new advances in the field.

关键词： asymmetric cell division peptide signaling phytohormonal signaling polarity proteins plant development Transcription factors

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MINI-EX:Integrative inference of single-cell gene regulatory networks in plants

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Molecular Plant 2022年第11期15卷 1807-1824页

作者： Camilla Ferrari Nicolás Manosalva Pérez Klaas Vandepoele Department of Plant Biotechnology and Bioinformatics Ghent University9052 GhentBelgium Center for Plant Systems Biology VIB9052 GhentBelgium Bioinformatics Institute Ghent Ghent University9052 GhentBelgium

Multicellular organisms,such as plants,are characterized by highly specialized and tightly regulated cell populations,establishing specific morphological structures and executing distinct functions.Gene regulatory networks(GRNs)describe condition-specific interactions of Transcription factors(TFs)regulating the expression of target genes,underpinning these specific functions.As efficient and validated methods to identify cell-type-specific GRNs from single-cell data in plants are lacking,limiting our understanding of the organization of specific cell types in both model species and crops,we developed MINI-EX(Motif-Informed Network Inference based on single-cell EXpression data),an integrative approach to infer cell-type-specific networks in plants.MINI-EX uses single-cell transcriptomic data to define expression-based networks and integrates TF motif information to filter the inferred regulons,resulting in networks with increased accuracy.Next,regulons are assigned to different cell types,leveraging cell-specific expression,and candidate regulators are prioritized using network centrality measures,functional annotations,and expression specificity.This embedded prioritization strategy offers a unique and efficient means to unravel signaling cascades in specific cell types controlling a biological process of interest.We demonstrate the stability of MINI-EX toward input data sets with low number of cells and its robustness toward missing data,and show that it infers state-of-the-art networks with a better performance compared with other related single-cell network tools.MINI-EX successfully identifies key regulators controlling root development in Arabidopsis and rice,leaf development in Arabidopsis,and ear development in maize,enhancing our understanding of cell-type-specific regulation and unraveling the roles of different regulators controlling the development of specific cell types in plants.

关键词： single-cell RNA-seq gene regulatory network Transcription factors systems biology

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WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1225-1239页

作者： Xiaomeng Gao Jieqiong You Yanling Gong Meng Yuan Haiying Zhu Liang Fang Hong Zhu Meidan Ying Qiaojun He Bo Yang Ji Cao Institute of Pharmacology and Toxicology Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China Department of Biology Southern University of Science and TechnologyShenzhen 518055China Cancer Center of Zhejiang University Hangzhou 310058China

The dysregulation of Transcription factors is widely associated with tumorigenesis.As the most well-defined transcription factor in multiple types of cancer,c-Myc can transform cells by transactivating various downstream genes.Given that there is no effective way to directly inhibit c-Myc,c-Myc targeting strategies hold great potential for cancer therapy.In this study,we found that WSB1,which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples,is a direct target gene of c-Myc,and can positively regulate c-Myc expression,which forms a feedforward circuit promoting cancer development.RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted cMyc expression through theβ-catenin pathway.Mechanistically,WSB1 affectedβ-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptorβ-TRCP recruitment,which inhibited the ubiquitination ofβ-catenin and transactivated c-Myc.Of interest,the effect of WSB1 on c-Myc was independent of its E3 ligase activity.Moreover,overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression.Thus,our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role,highlighting a potential c-Myc intervention strategy in cancer treatment.

关键词： Transcription factors c-Myc WSB1 Ubiquitinationproteasome pathway β-Catenin destruction complex Feedback loop Tumorigenesis Cancer treatment

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Transcriptome and carotenoid profiling of different varieties of Coffea arabica provides insights into fruit color formation

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Plant Diversity 2022年第3期44卷 322-334页

作者： Faguang Hu Xiaofei Bi Hongming Liu Xingfei Fu Yanan Li Yang Yang Xiaofang Zhang Ruirui Wu Guiping Li Yulan Lv Jiaxiong Huang Xinping Luo Rui Shi Institute of Tropical and Subtropical Cash Crops Yunnan Academy of Agricultural SciencesChina Key Laboratory for Forest Resources Conservation and Utilization in the Southwest Mountains of China Ministry of EducationSouthwest Forestry UniversityChina

The processability and ultimate quality of coffee(Coffea arabica)are determined by the composition of the matured fruits.The basis of genetic variation in coffee fruit quality could be explained by studying color formation during fruit maturation.Transcriptome profiling was conducted on matured fruits of four C.arabica varieties(orange colored fruits(ORF);purple colored fruits(PF);red colored fruits(RF)and yellow colored fruits(YF))to identify key color-regulating genes,biosynthesis pathways and Transcription factors implicated in fruit color formation.A total of 39,938 genes were identified in the transcriptomes of the four C.arabica varieties.In all,2745,781 and 1224 differentially expressed genes(DEGs)were detected in YF_vs_PF,YF_vs_RF and YF_vs_ORF,respectively,with 1732 DEGs conserved among the three pairwise groups.Functional annotation of the DEGs led to the detection of 28 and 82 key genes involved in the biosynthesis of carotenoids and anthocyanins,respectively.Key Transcription factors bHLH,MYB,NAC,MADS,and WRKY implicated in fruit color regulation were detected.The high expression levels of gene-LOC113688784(PSY),gene-LOC113730013(b-CHY),gene-LOC113728842(CCD7),gene-LOC113689681(NCED)and gene-LOC113729473(ABA2)in YF may have accounted for the yellow coloration.The differential expression of several anthocyanin and carotenoid-specific genes in the fruits substantially account for the purple(PF),red(RF),and orange(ORF)colorations.This study provides important insights into fruit color formation and variations in C.arabica and will help to develop coffee varieties with specific color and quality traits.

关键词： Coffee Carotenoids Anthocyanins Transcription factors Functional enrichment

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transcriptional control of pancreaticβ-cell identity and plasticity during the pathogenesis of type 2 diabetes

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Journal of Genetics and Genomics 2022年第4期49卷 316-328页

作者： Ziyin Zhang Yue Gao Zhuo-Xian Meng Department of Pathology and Pathophysiology and Department of Geriatrics of Affiliated Hangzhou First People’s Hospital Zhejiang University School of MedicineHangzhouChina Key Laboratory of Disease Proteomics of Zhejiang Province Zhejiang University School of MedicineHangzhouZhejiang310058China Department of Geriatrics Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouZhejiang310006China

Type 2 diabetes(T2D)is caused by insulin resistance and insufficient insulin secretion.Evidence has increasingly indicated that pancreaticβ-cell dysfunction is the primary determinant of T2D disease progression and remission.High plasticity is an important feature of pancreaticβ-cells.During T2D development,pancreaticβ-cells undergo dynamic adaptation.Althoughβ-cell death/apoptosis in later-stage T2D is the major cause ofβ-cell dysfunction,recent studies have revealed thatβ-cell dedifferentiation and reprogramming,which play critical roles inβ-cell functional regulation in the early and middle T2D progression stages,are characterized by(i)a loss of matureβ-cell-enriched genes;(ii)dedifferentiation to a progenitor-like state;and(iii)transdifferentiation into other cell types.The roles of Transcription factors(TFs)in the establishment and maintenance ofβ-cell identity during pancreatic development have been extensively studied.Here,we summarize the roles and underlying mechanisms of TFs in the maintenance ofβ-cell identity under physiological and type 2 diabetic conditions.Several feasible approaches for restoring islet functions are also discussed.A better understanding of the transcriptional control ofβ-cell identity and plasticity will pave the way for developing more effective strategies,such asβ-cell regeneration therapy,to treat T2D and associated metabolic disorders.

关键词： Type 2 diabetes Pancreaticβ-cell Transcription factors Dedifferentiation Transdifferentiation Redifferentiation

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transcriptional regulation analysis reveals the complexity of metamorphosis in the Pacific oyster(Crassostrea gigas)

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Marine Life Science & Technology 2023年第4期5卷 467-477页

作者： Fei Xu Shaoxi Deng Daria Gavriouchkina Guofan Zhang CAS and Shandong Province Key Laboratory of Experimental Marine Biology Center for Ocean Mega-ScienceInstitute of OceanologyChinese Academy of SciencesQingdao 266071China Laoshan Laboratory Qingdao 266237China Shandong Technology Innovation Center of Oyster Seed Industry Qingdao 266105China School of Energy and Environment and State Key Laboratory of Marine Pollution City University of Hong KongHong Kong 999077China Molecular Genetics Unit Okinawa Institute of Science and Technology Graduate UniversityOkinawa 904-0495Japan UK Dementia Research Institute University College LondonLondon WC1E 6BTUK

Many marine invertebrate phyla are characterized by indirect development.These animals transit from planktonic larvae to benthic spats via settlement and metamorphosis,which contributes to their adaption to the marine environment.Studying the biological process of metamorphosis is,thus,key to understanding the origin and evolution of indirect development.Although numerous studies have been conducted on the relationship between metamorphosis and the marine environment,microorganisms,and neurohormones,little is known about gene regulation network(GRN)dynamics during metamorphosis.Metamorphosis-competent pediveligers of the Pacific oyster Crassostrea gigas were assayed in this study.By assaying gene expression patterns and open chromatin region changes of different samples of larvae and spats,the dynamics of molecular regulation during metamorphosis were examined.The results indicated significantly different gene regulation networks before,during and post-metamorphosis.Genes encoding membrane-integrated receptors and those related to the remodeling of the nervous system were upregulated before the initiation of metamorphosis.Massive biogenesis,e.g.,of various enzymes and structural proteins,occurred during metamorphosis as inferred from the comprehensive upregulation of the protein synthesis system post epinephrine stimulation.Hierarchical downstream gene networks were then stimulated.Some Transcription factors,including homeobox,basic helix–loop–helix and nuclear receptors,showed different temporal response patterns,suggesting a complex GRN during the transition stage.Nuclear receptors,as well as their retinoid X receptor partner,may participate in the GRN controlling oyster metamorphosis,indicating an ancient role of the nuclear receptor regulation system in animal metamorphosis.

关键词： Gene regulation network Indirect development Lophotrochozoa Nuclear receptors Neurohormones Protein synthesis Transcription factors

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A Vertex Network Model of Arabidopsis Leaf Growth

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Communications on Applied Mathematics and Computation 2024年第1期6卷 454-488页

作者： Luke Andrejek Janet Best Ching-Shan Chou Aman Husbands Department of Mathematics The Ohio State UniversityColumbusOHUSA Department of Biology The University of PennsylvaniaPhiladelphiaPAUSA

Biology provides many examples of complex systems whose properties allow organisms to develop in a highly reproducible,or robust,manner.One such system is the growth and development of flat leaves in Arabidopsis thaliana.This mechanistically challenging process results from multiple inputs including gene interactions,cellular geometry,growth rates,and coordinated cell divisions.To better understand how this complex genetic and cellular information controls leaf growth,we developed a mathematical model of flat leaf production.This two-dimensional model describes the gene interactions in a vertex network of cells which grow and divide according to physical forces and genetic information.Interestingly,the model predicts the presence of an unknown additional factor required for the formation of biologically realistic gene expression domains and iterative cell division.This two-dimensional model will form the basis for future studies into robustness of adaxial-abaxial patterning.

关键词： Robustness Adaxial-abaxial patterning Mathematical modeling Gene regulatory networks(GRNs) Transcription factors Small RNAs

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The anti-cancerous mechanism of licochalcone A on human hepatoma cell HepG2 based on the miRNA omics

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Food Science and Human Wellness 2023年第4期12卷 1136-1148页

作者： Jun Wang Xiuxiu Zhang Zhijing Ni Elnur Elam Kiran Thakur Kexin Li Chuyan Wang Jianguo Zhang Zhaojun Wei School of Biological Food and Environment Hefei UniversityHefei 230601China School of Food and Biological Engineering Hefei University of TechnologyHefei 230009China School of Biological Science and Engineering Ningxia Key Laboratory for the Development and Application of Microbial Resources in Extreme EnvironmentsNorth Minzu UniversityYinchuan 750021China

To explore the function of licochalcone A as an anticancer phytochemical on HepG2 cells and investigate its potential mechanisms,we analyzed the microRNAs(miRNAs)expression profile of HepG2 cells in response to licochalcone A(70μmol/L)in vitro.102 dysregulated miRNAs were detected,and SP1 was expected as the transcription factor that regulates the functions of most screened miRNAs.A sum of 431 targets,the overlap of predicted mRNAs from TargetScan,miRDB,and miRtarbase were detected as the targets for these dysregulated miRNAs.FoxO signaling pathway was the hub pathway for the targets.A protein-protein interaction network was structured on the STRING platform to discover the hub genes.Among them,PIK3R1,CDC42,ESR1,SMAD4,SUMO1,KRAS,AGO1,etc.were screened out.Afterwards,the miRNA-target networks were established to screen key dysregulated miRNAs.Two key miRNAs(hsa-miR-133b and hsa-miR-145-5p)were filtered.Finally,the miRNA-target-transcription factor networks were constructed for these key miRNAs.The networks for these key miRNAs included three and two Transcription factors,respectively.These identified miRNAs,Transcription factors,targets,and regulatory networks may offer hints to understand the molecular mechanism of licochalcone A as a natural anticarcinogen.

关键词： Licochalcone A HepG2 cells Dysregulated miRNAs Transcription factors Targets Regulatory networks

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The role of glutathione-mediated triacylglycerol synthesis in the response to ultra-high cadmium stress in Auxenochlorella protothecoides

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Journal of Environmental Sciences 2021年第10期33卷 58-69页

作者： Chao Xing Jinyu Li Sin Man Lam Hongli Yuan Guanghou Shui Jinshui Yang State Key Laboratory of Agrobiotechnology and Key Laboratory of Soil Microbiology Ministry of AgricultureCollege of Biological SciencesChina Agricultural UniversityBeijing 100193China State Key Laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China Lipidall Technologies Company Limited Changzhou 213022China

Under ultra-high cadmium(Cd)stress,large amounts of glutathione are produced in Auxenochlorella protothecoides UTEX 2341,and the lipid content increases significantly.Glutathione is the best reductant that can effectively remove Cd,but the relationship between lipid accumulation and the cellular response to Cd stress has not been ascertained.Integrating analyses of the transcriptomes and lipidomes,the mechanism of lipid accumulation to Cd tolerance were studied from the perspectives of metabolism,transcriptional regulation and protein glutathionylation.Under Cd stress,basic metabolic pathways,such as purine metabolism,translation and pre-m RNA splicing process,were inhibited,while the lipid accumulation pathway was significantly activated.Further analysis revealed that the Transcription factors(TFs)and genes related to lipid accumulation were also activated.Analysis of the TF interaction sites showed that ABI5,MYBrel and NF-YB could further regulate the expression of diacylglycerol acyltransferase through glutathionylation/deglutathionylation,which led to increase of the triacylglycerol(TAG)content.Lipidomes analysis showed that TAG could help maintain lipid homeostasis by adjusting its saturation/unsaturation levels.This study for the first time indicated that glutathione could activate TAG synthesis in microalga A.protothecoides,leading to TAG accumulation and glutathione accumulation under Cd stress.Therefore,the accumulation of TAG and glutathione can confer resistance to high Cd stress.This study provided insights into a new operation mode of TAG accumulation under heavy metal stress.

关键词： Cd stress Microalgae Glutathionylation Transcription factors Triacylglycerol

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