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Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer

Cancer Biology & Medicine 2024年第1期21卷 83-103页

作者： Yumei Wang Haiyan Wang Wei Shao Yuhui Chen Yu Gui Chao Hu Xiaohong Yi Lijun Huang Shasha Li Dong Wang School of Basic Medical Sciences State Key Laboratory of Southwestern Chinese Medicine ResourcesChengdu University of Traditional Chinese MedicineChengdu 611137China Department of Pathology School of MedicineQinghai UniversityXining 810001China Omics Biosciences Inc Beijing 100871China Laboratory of Integrative Medicine Clinical Research Center for BreastState Key Laboratory of BiotherapyWest China HospitalSichuan University and Collaborative Innovation CenterChengdu 610041China State Key Laboratory of Southwestern Chinese Medicine Resources School of PharmacyChengdu University of Traditional Chinese MedicineChengdu 611137China Department of Endocrinology and Metabolism Guangdong Provincial Key Laboratory of Diabetology&Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity ResearchMedical Center for Comprehensive Weight ControlThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China

Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive.It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.Methods:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators.Then,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.Results:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific functions.We discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and CBX3.Moreover,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation.Notably,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.Conclusions:Our work deciphered the extensive regulation among hundreds of epigenetic regulators.The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

关键词： Epigenetic regulators breast cancer regulatory network HTS^(2)

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regulatory network established by transcription factors transmits drought stress signals in plant

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Stress Biology 2022年第1期2卷 361-382页

作者： Yongfeng Hu Xiaoliang Chen Xiangling Shen Key Laboratory of Three Gorges Regional Plant Genetics and Germplasm Enhancement Biotechnology Research CenterChina Three Gorges UniversityYichang 443002HubeiChina

Plants are sessile organisms that evolve with a flexible signal transduction system in order to rapidly respond to environmental changes.Drought,a common abiotic stress,affects multiple plant developmental processes especially growth.In response to drought stress,an intricate hierarchical regulatory network is established in plant to survive from the extreme environment.The transcriptional regulation carried out by transcription factors(TFs)is the most important step for the establishment of the network.In this review,we summarized almost all the TFs that have been reported to participate in drought tolerance(DT)in plant.Totally 466 TFs from 86 plant species that mostly belong to 11 families are collected here.This demonstrates that TFs in these 11 families are the main transcriptional regulators of plant DT.The regulatory network is built by direct protein-protein interaction or mutual regulation of TFs.TFs receive upstream signals possibly via post-transcriptional regulation and output signals to downstream targets via direct binding to their promoters to regulate gene expression.

关键词： Plant Drought tolerance Transcription factor regulatory network Direct target

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Expression and regulatory network of long noncoding RNA in rats after spinal cord hemisection injury

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Neural Regeneration Research 2022年第10期17卷 2300-2304页

作者： Wei Liu Jin-Cheng Tao Sheng-Ze Zhu Chao-Lun Dai Ya-Xian Wang Bin Yu Chun Yao Yu-Yu Sun Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina Medical College Nantong UniversityNantongJiangsu ProvinceChina Department of Orthopedics Nantong Third People’s HospitalNantong UniversityNantongJiangsu ProvinceChina

Long noncoding RNAs(lncRNAs)participate in a variety of biological processes and diseases.However,the expression and function of lncRNAs after spinal cord injury has not been extensively analyzed.In this study of right side hemisection of the spinal cord at T10,we detected the expression of lncRNAs in the proximal tissue of T10 lamina at different time points and found 445 lncRNAs and 6522 mRNA were differentially expressed.We divided the differentially expressed lncRNAs into 26 expression trends and analyzed Profile 25 and Profile 2,the two expression trends with the most significant difference.Our results showed that the expression of 68 lncRNAs in Profile 25 rose first and remained high 3 days post-injury.There were 387 mRNAs co-expressed with the 68 lncRNAs in Profile 25.The co-expression network showed that the co-expressed genes were mainly enriched in cell division,inflammatory response,FcγR-mediated cell phagocytosis signaling pathway,cell cycle and apoptosis.The expression of 56 lncRNAs in Profile2 first declined and remained low after 3 days post-injury.There were 387 mRNAs co-expressed with the 56 lncRNAs in Profile 2.The co-expression network showed that the co-expressed genes were mainly enriched in the chemical synaptic transmission process and in the signaling pathway of neuroactive ligand-receptor interaction.The results provided the expression and regulatory network of the main lncRNAs after spinal cord injury and clarified their co-expressed gene enriched biological processes and signaling pathways.These findings provide a new direction for the clinical treatment of spinal cord injury.

关键词： bioinformatic analysis biological process gene ontology analysis inflammatory response Kyoto encyclopedia of genes and genomes analysis long noncoding RNAs regulatory network RNA sequencing spinal cord injury synaptic transmission

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Identification of the target genes of AhTWRKY24 and AhTWRKY106 transcription factors reveals their regulatory network in Arachis hypogaea cv.Tifrunner using DAP-seq

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Oil Crop Science 2023年第2期8卷 89-96页

作者： Meiran Li Mingwei Chen Yongli Zhang Longgang Zhao Jiancheng Zhang Hui Song Key Laboratory of National Forestry and Grassland Administration on Grassland Resources and Ecology in the Yellow River Delta College of Grassland ScienceQingdao Agricultural UniversityQingdaoChina Qingdao Key Laboratory of Specialty Plant Germplasm Innovation and Utilization in Saline Soils of Coastal Beach College of Grassland ScienceQingdao Agricultural UniversityQingdaoChina High-efficiency Agricultural Technology Industry Research Institute of Saline and Alkaline Land of Dongying Qingdao Agricultural UniversityQingdaoChina Shandong Peanut Research Institute QingdaoChina

WRKY transcription factors(TFs)have been identified as important core regulators in the responses of plants to biotic and abiotic stresses.Cultivated peanut(Arachis hypogaea)is an important oil and protein crop.Previous studies have identified hundreds of WRKY TFs in peanut.However,their functions and regulatory networks remain unclear.Simultaneously,the AdWRKY40 TF is involved in drought tolerance in Arachis duranensis and has an orthologous relationship with the AhTWRKY24 TF,which has a homoeologous relationship with AhTWRKY106 TF in A.hypogaea cv.Tifrunner.To reveal how the homoeologous AhTWRKY24 and AhTWRKY106 TFs regulate the downstream genes,DNA affinity purification sequencing(DAP-seq)was performed to detect the binding sites of TFs at the genome-wide level.A total of 3486 downstream genes were identified that were collectively regulated by the AhTWRKY24 and AhTWRKY106 TFs.The results revealed that W-box elements were the binding sites for regulation of the downstream genes by AhTWRKY24 and AhTWRKY106 TFs.A gene ontology enrichment analysis indicated that these downstream genes were enriched in protein modification and reproduction in the biological process.In addition,RNA-seq data showed that the AhTWRKY24 and AhTWRKY106 TFs regulate differentially expressed genes involved in the response to drought stress.The AhTWRKY24 and AhTWRKY106 TFs can specifically regulate downstream genes,and they nearly equal the numbers of downstream genes from the two A.hypogaea cv.Tifrunner subgenomes.These results provide a theoretical basis to study the functions and regulatory networks of AhTWRKY24 and AhTWRKY106 TFs.

关键词： DAP-Seq Homoeolog Peanut regulatory network WRKY transcription Factor

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MdbHLH162 connects the gibberellin and jasmonic acid signals to regulate anthocyanin biosynthesis in apple

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Journal of Integrative Plant Biology 2024年第2期66卷 265-284页

作者： Jian-Ping An Rui-Rui Xu Xiao-Na Wang Xiao-Wei Zhang Chun-Xiang You Yuepeng Han Apple technology innovation center of Shandong Province College of Horticulture Science and EngineeringShandong Agricultural UniversityTai-An 271018China CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture Wuhan Botanical GardenHubei Hongshan LaboratoryThe Innovative Academy of Seed Design of Chinese Academy of SciencesWuhan 430074China College of Biology and Oceanography Weifang UniversityWeifang 261061China

Anthocyanins are secondary metabolites induced by environmental stimuli and developmental signals.The positive regulators of anthocyanin biosynthesis have been reported,whereas the anthocyanin repressors have been neglected.Although the signal transduction pathways of gibberellin(GA)and jasmonic acid(JA)and their regulation of anthocyanin biosynthesis have been investigated,the cross-talk between GA and JA and the antagonistic mechanism of regulating anthocyanin biosynthesis remain to be investigated.In this study,we identified the anthocyanin repressor MdbHLH162 in apple and revealed its molecular mechanism of regulating anthocyanin biosynthesis by integrating the GA and JA signals.MdbHLH162 exerted passive repression by interacting with MdbHLH3 and MdbHLH33,which are two recognized positive regulators of anthocyanin biosynthesis.MdbHLH162 negatively regulated anthocyanin biosynthesis by disrupting the formation of the anthocyanin-activated MdMYB1-MdbHLH3/33complexes and weakening transcriptional activation of the anthocyanin biosynthetic genes MdDFR and MdUF3GT by MdbHLH3 and MdbHLH33.The GA repressor MdRGL2a antagonized MdbHLH162-mediated inhibition of anthocyanins by sequestering MdbHLH162 from the MdbHLH162-MdbHLH3/33 complex.The JA repressors MdJAZ1 and MdJAZ2 interfered with the antagonistic regulation of MdbHLH162 by MdRGL2a by titrating the formation of the MdRGL2a-MdbHLH162 complex.Our findings reveal that MdbHLH162 integrates the GA and JA signals to negatively regulate anthocyanin biosynthesis.This study provides new information for discovering more anthocyanin biosynthesis repressors and explores the cross-talk between hormone signals.

关键词： anthocyanin biosynthesis bHLH transcription factor gibberellin jasmonic acid regulatory network transcriptional regulation

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Small but influential:the role of microRNAs on gene regulatory network and 3′UTR evolution

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Journal of Genetics and Genomics 2009年第1期36卷 1-6页

作者： Rui Zhang Bing Su State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology and Kunming Primate Research Center Chinese Academy of Sciences Kunming 650223 China Graduate School of Chinese Academy of Sciences Beijing 100039 China

MicroRNAs （miRNAs） are endogenous -22 nucleotide noncoding RNAs that regulate the expression of complementary messenger RNAs （mRNAs）. Thousands of miRNA genes have been found in diverse species, and many of them are highly conserved. With the miRNA roles identified in nearly all aspects of biological processes, evidence is mounting that miRNAs could represent a new layer of regulatory network, and their regulatory effect might be much more pervasive than previously suspected. Here we focus on the posttranscriptional level gene regulation of miRNAs in animals and review how the miRNAs act to sustain and shape up the expression profiles of specific cell types; how the miRNAs integrate into the existing gene regulatory networks; and how the miRNAs influence the evolution of 3＇UTR of mammalian mRNAs.

关键词： miRNA gene expression regulatory network 3＇UTR evolution

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Single-cell transcriptome sequencing reveals the mechanism regulating rice plumule development

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The Crop Journal 2024年第3期12卷 688-697页

作者： Mingdong Zhu Meng Zhang Kunyong Huang Feifei Lu Hong Wang Shaolu Zhao Yinghong Yu Shaoqing Tang Haining Wu Peisong Hu Xiangjin Wei State Key Laboratory of Rice Biology and Breeding China National Center for Rice ImprovementChina National Rice Research InstituteHangzhou 310006ZhejiangChina b State Key Laboratory of Hybrid Rice Hunan Rice Research InstituteHunan Academy of Agricultural SciencesChangsha 410125HunanChina Hunan Provincial Key Laboratory of Plant Functional Genomics and Developmental Regulation College of BiologyHunan UniversityChangsha 410082HunanChina Hubei University Wuhan 430062HubeiChina

Seed plumules comprise multiple developing tissues and are key sites for above-ground plant organ morphogenesis.Here,the spatial expression of genes in developing rice seed plumules was characterized by single-cell transcriptome sequencing in Zhongjiazao 17,a popular Chinese indica rice cultivar.Of 15 cell clusters,13 were assigned to cell types using marker genes and cluster-specific genes.Marker genes of multiple cell types were expressed in several clusters,suggesting a complex developmental system.Some genes for signaling by phytohormones such as abscisic acid were highly expressed in specific clusters.Various cis-elements in the promoters of genes specifically expressed in cell clusters were calculated,and some key hormone-related motifs were frequent in certain clusters.Spatial expression patterns of genes involved in rapid seed germination,seedling growth,and development were identified.These findings enhanced our understanding of cellular diversity and specialization within plumules of rice,a monocotyledonous model crop.

关键词： Rice Plumule Single-cell sequencing regulatory network

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Noise control and utility:From regulatory network to spatial patterning

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Science China Mathematics 2020年第3期63卷 425-440页

作者： Qing Nie Lingxia Qiao Yuchi Qiu Lei Zhang Wei Zhao Department of Mathematics University of California at IrvineIrvineCA 92697USA Department of Developmental and Cell Biology NSF-Simons Center for Multiscale Cell Fate ResearchUniversity of California at IrvineIrvineCA 92697USA Beijing International Center for Mathematical Research Peking UniversityBeijing 100871China Center for Quantitative Biology Peking UniversityBeijing 100871China

Stochasticity(or noise) at cellular and molecular levels has been observed extensively as a universal feature for living systems. However, how living systems deal with noise while performing desirable biological functions remains a major mystery. regulatory network configurations, such as their topology and timescale, are shown to be critical in attenuating noise, and noise is also found to facilitate cell fate decision. Here we review major recent findings on noise attenuation through regulatory control, the benefit of noise via noise-induced cellular plasticity during developmental patterning and summarize key principles underlying noise control.

关键词： noise attenuation regulatory network design principle spatial patterning

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Molecular regulatory network of Flowering by Photoperiod and Temperature in Rice

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Rice science 2012年第3期19卷 169-176页

作者： SONG Yuan-li LUAN Wei-jiang Tianjin Key Laboratory of Cyto-Genetical&Molecular Regulation/College of Life Science Tianjin Normal UniversityTianjin 300387China

Plants have an ability to flower under optimal seasonal conditions to ensure reproductive success. Photoperiod and temperature are two important season-dependent factors of plant flowering. The floral transition of plants depends on accurate measurement of changes in photoperiod and temperature. Recent advances in molecular biology and genetics on Arabidopsis and rice reveals that the regulation of plant flowering by photoperiod and temperature are involved in a complicated gene network with different regulatory pathways, and new evidence and understanding were provided in the regulation of rice flowering. Here, we summarize and analyze different flowering regulatory pathways in detail in rice based on previous studies and our results, including short-day promotion, long-day suppression, long-day induction of flowering, night break, different light-quality and temperature regulation pathways.

关键词： rice flowering photoperiod temperature regulatory network

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Chromatin accessibility landscapes revealed the subgenome-divergent regulation networks during wheat grain development

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aBIOTECH 2023年第1期4卷 8-19页

作者： Hongcui Pei Yushan Li Yanhong Liu Pan Liu Jialin Zhang Xueni Ren Zefu Lu Institute of Crop Sciences Chinese Academy of Agricultural SciencesBeijing 100081China

Development of wheat(Triticum aestivum L.)grain mainly depends on the processes of starch synthesis and storage protein accumulation,which are critical for grain yield and quality.However,the regulatory network underlying the transcriptional and physiological changes of grain development is still not clear.Here,we combined ATAC-seq and RNA-seq to discover the chromatin accessibility and gene expression dynamics during these processes.We found that the chromatin accessibility changes are tightly associated with differential transcriptomic expressions,and the proportion of distal ACRs was increased gradually during grain development.Specific transcription factor(TF)binding sites were enriched at different stages and were diversified among the 3 subgenomes.We further predicted the potential interactions between key TFs and genes related with starch and storage protein biosynthesis and found different copies of some key TFs played diversified roles.Overall,our findings have provided numerous resources and illustrated the regulatory network during wheat grain development,which would shed light on the improvement of wheat yields and qualities.

关键词： Wheat Chromatin accessibility Subgenome-divergence regulatory network Grain development

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