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Exploring noncoding variants in genetic diseases:from detection to functional insights

Journal of genetics and Genomics 2024年第2期51卷 111-132页

作者： Ke Wu Fengxiao Bu Yang Wu Gen Zhang Xin Wang Shunmin He Mo-Fang Liu Runsheng Chen Huijun Yuan Institute of Rare Diseases West China Hospital of Sichuan UniversityChengduSichuan 610041China key laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhouZhejiang 310024China key laboratory of RNA Biology Center for Big Data Research in HealthInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State key laboratory of molecular Biology State Key Laboratory of Cell BiologyShanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai 200031China

Previous studies on genetic diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants. These variants can impact gene expression, regulation, and chromatin conformation, thereby contributing to disease pathogenesis. Understanding the mechanisms that underlie the impact of noncoding variants on genetic diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies. The intricacies of noncoding regions introduce a multitude of challenges and research opportunities. In this review, we introduce a spectrum of noncoding variants involved in genetic diseases, along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome. We will delve into the research challenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.

关键词： Noncoding variation Genetic disease Research approach Challenge

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PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton,modulating emotional behavior

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Zoological Research 2024年第3期45卷 535-550页

作者： Laidong Yu Fangfang Zeng Mengshu Fan Kexuan Zhang Jingjing Duan Yalu Tan Panlin Liao Jin Wen Chenyu Wang Meilin Wang Jialong Yuan Xinxin Pang Yan Huang Yangzhou Zhang Jia-Da Li Zhuohua Zhang Zhonghua Hu Hunan key laboratory of molecular Precision medicine Department of Critical Care MedicineXiangya HospitalCentral South UniversityChangshaHunan 410008China Center for Medical genetics and Hunan key laboratory of Medical genetics School of Life SciencesCentral South UniversityChangshaHunan 410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan 410008China Hunan Provincial Clinical Research Center for Critical Care medicine Xiangya HospitalCentral South UniversityChangshaHunan 410008China Hunan key laboratory of Animal Models for Human Diseases School of Life SciencesCentral South UniversityChangshaHunan 410008China MOE key Lab of Rare Pediatric Diseases School of Life SciencesCentral South UniversityChangshaHunan 410008China Department of Neurosciences University of South China Medical SchoolHengyangHunan 421001China

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain *** abnormalities,such as defects in the density and morphology of postsynaptic dendritic spines,underlie the pathology of various neuropsychiatric *** 17(PCDH17)is associated with major mood disorders,including bipolar disorder and ***,the molecular mechanisms by which PCDH17 regulates spine number,morphology,and behavior remain *** this study,we found that PCDH17 functions at postsynaptic sites,restricting the number and size of dendritic spines in excitatory *** overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety-and depression-like behaviors in ***,PCDH17 interacts with actin-relevant proteins and regulates actin filament(F-actin)***,PCDH17 binds to ROCK2,increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3(Ser3).Inhibition of ROCK2 activity with belumosudil(KD025)ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression,suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine ***,these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior,providing pathological insights into the neurobiological basis of mood disorders.

关键词： Synapse development Dendritic spine Mood disorder Actin cytoskeleton Animal behavior

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Preparation and interaction mechanism analysis of single‑chain fragment variables against phenylethanolamine A

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Animal Diseases 2024年第2期4卷 127-137页

作者： Long Li Ren Hou Huaming Li Shiyun Han Jixiang Liang Yu Si Dapeng Peng State key laboratory of Agricultural Microbiology National Reference Laboratory of Veterinary Drug Residues(HZAU)and MOA Key Laboratory for Detection of Veterinary Drug ResiduesHuazhong Agricultural UniversityWuhan 430070PR China key laboratory of Preventive Veterinary medicine in Hubei Province The Cooperative Innovation Center for Sustainable Pig ProductionWuhan 430070China Hubei Topgene Biotechnology Co. Ltd.Wuhan BranchWuhanHubei 430070China shenzhen Institute of Nutrition and Health Huazhong Agricultural UniversityShenzhenGuangdong 518000China shenzhen Branch Guangdong Laboratory for Lingnan Modern AgricultureAgricultural Genomics Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhenGuangdong 518000China

This is the first report on the screening,expression,and recognition mechanism analysis of single-chain fragment variable(scFv)against phenylethanolamine A(PEAA),a newly emergedβ-adrenergic agonist illegally used as a feed additive for growth *** PEAA-specific scFv scFv,called scFv-32,was screened from hybridoma cell lines by phage display and was found to be optimally expressed in the *** *** ic-ELISA results revealed an IC_(50)value of 10.34μg/L for scFv-32 and no cross-reactivity with otherβ-adrenergic *** modeling and molecular docking revealed the key binding sites VAL178,TYP228,and *** hydrogen bond,two pisigma bonds,and one pi-pi bond maintain the formation of the antibody‒drug *** scanning mutagenesis of the three predicted key binding sites showed that the mutants completely lost their recognition activity,which confirmed the accuracy of the theoretical *** results are valuable for the preparation of scFvs and the analysis of the molecular recognition mechanism of antigen-antibodies.

关键词： Phenylethanolamine A ScFv Recognition mechanism Homology modeling molecular docking

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A novel deep generative model for mRNA vaccine development: Designing 5′ UTRs with N1-methyl-pseudouridine modification

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1814-1826页

作者： Xiaoshan Tang Miaozhe Huo Yuting Chen Hai Huang Shugang Qin Jiaqi Luo Zeyi Qin Xin Jiang Yongmei Liu Xing Duan Ruohan Wang Lingxi Chen Hao Li Na Fan Zhongshan He Xi He Bairong Shen Shuai Cheng Li Xiangrong Song Institute of Systems genetics Department of Critical Care MedicineFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China Department of Computer Science City University of Hong KongHong Kong 99907China Department of Biology Brandeis UniversityBostonMA 02453USA

Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA ***,the N1-methyl-pseudouridine(m1)modification of mRNA can impact the translation efficiency of the 5'*** discovered that the optimal 5'UTR for m1y-modified mRNA(m1y-5'UTR)differs significantly from its unmodified counterpart,high-lighting the need for a specialized tool for designing mly-5'UTRs rather than directly utilizing high-expression endogenous gene 5'*** response,we developed a novel machine learning-based tool,Smart5UTR,which employs a deep generative model to identify superior m1y-5'UTRs in *** tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing *** a result,Smart5UTR can successfully design superior 5'UTRs,greatly benefiting mRNA vaccine ***,Smart5UTR-designed superior 5'UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2,surpassing the performance of vaccines using high-expression endogenous gene 5'UTRs.

关键词： mRNA vaccine Machine learning 5'UTR mRNA design Sequence design N1-Methyl-pseudouridine COVID-19 SARS-CoV-2

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Meiotic nuclear divisions 1 suppresses the proliferation and invasion of pancreatic cancer cells via regulating H2A.X variant histone

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BIOCELL 2024年第1期48卷 111-122页

作者： DONGQIN WANG YAN SHI ZHIQIANG WANG JING ZHANG LUYAO WANG HONGYU MA SHUHUA SHI XIAOFU LIAN HUA HUANG XIAOJING WANG CHAOQUN LIAN Anhui Province key laboratory of Clinical and Preclinical Research in Respiratory Disease Molecular Diagnosis CenterThe Department of Pulmonary Critical Care MedicineFirst Affiliated Hospital of Bengbu Medical CollegeBengbu233030China Department of genetics School of Life SciencesBengbu Medical CollegeBengbu233000China Department of Clinical medicine Bengbu Medical CollegeBengbu233030China Research Center of Clinical laboratory Science Bengbu Medical CollegeBengbu233030China

Introduction:Among all malignant tumors of the digestive system,pancreatic carcinoma exhibits the highest mortality ***,prevention and effective treatment are urgent issues that need to be ***:The study focused on meiotic nuclear divisions 1(MND1),integrating data from the Gene Expression Profiling Interactive Analysis(GEPIA)database with prognostic survival ***,experiments at cellular level were employed to demonstrate the effect of MND1 on the proliferation and migration of *** small-molecule inhibitor of MND1 was used to suppress the migration of PC cells by knocking down MND1 using small interfering RNA(siRNA)in Patu-8988 and Panc1 cell ***:The results of Cell Counting Kit-8 indicated that the suppression of MND1 resulted in a decrease in cell *** healing and Transwell assays revealed that MND1 knockdown reduced cell migration and *** cytometry revealed that inhibiting MND1 hindered the cell ***,MND1 could stimulate the proliferation,migration,and invasion of Patu-8988 and Panc1 cells by increasing the expression of ***,MND1 had a positive effect on H2AFX expression in PC *** MND1 expression suggests the low overall survival rate of individuals diagnosed with ***:These findings suggest that MND1 has the potential to be a gene with the ability to accurately diagnose and treat PC.

关键词： Pancreatic carcinoma MND1 H2AFX Cell cycle

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Temporal control of the Aux/IAA genes BnIAA32 and BnIAA34 mediates Brassica napus dual shade responses

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Journal of Integrative Plant Biology 2024年第5期66卷 928-942页

作者： Yafei Li Yiyi Guo Yue Cao Pengguo Xia Dongqing Xu Ning Sun Lixi Jiang Jie Dong Institute of Crop Science College of Agriculture and BiotechnologyZhejiang UniversityHangzhou 310058China key laboratory of Plant Secondary Metabolism and Regulation of Zhejiang Province College of Life Sciences and MedicineZhejiang Sci-TechUniversityHangzhou310018China State key laboratory of Crop genetics and Germplasm Enhancement College of AgricultureNanjing Agricultural UniversityNanjing 210095China key laboratory of Growth Regulation and Transformation Research of Zhejiang Province School of Life SciencesWestlake UniversityHangzhou 310024China

Precise responses to changes in light quality are crucial for plant growth and *** example,hypocotyls of shade-avoiding plants typically elongate under shade *** this typical shade-avoidance response(TSR)has been studied in Arabidopsis(Arabidopsis thaliana),the molecular mechanisms underlying shade tolerance are poorly *** we report that ***(Brassica napus)seedlings exhibit dual shade *** addition to the TSR,*** seedlings also display an atypical shade response(ASR),with shorter hypocotyls upon perception of early-shade ***-wide selective sweep analysis indicated that ASR is associated with light and auxin ***,genetic studies demonstrated that phytochrome A(BnphyA)promotes ASR,whereas BnphyB inhibits *** ASR,YUCCA8 expression is activated by early-shade cues,leading to increased auxin *** inhibits hypocotyl elongation,as young *** seedlings are highly sensitive to ***,two non-canonical AUXIN/INDOLE-3-ACETIC ACID(Aux/IAA)repressor genes,BnIAA32 and BnIAA34,are expressed during this early ***32 and BnIAA34 inhibit hypocotyl elongation under shade conditions,and mutations in BnIAA32 and BnIAA34 suppress ***,our study demonstrates that the temporal expression of BnIAA32 and BnIAA34 determines the behavior of *** seedlings following shade-induced auxin biosynthesis.

关键词： Brassica napus high-density planting IAA32/34 light signal transduction shade response temporal gene expression

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FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury

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Military Medical Research 2024年第4期11卷 521-542页

作者： Mi Zhou Yang-Wu-Yue Liu Yu-Hang He Jing-Yu Zhang Hao Guo Hao Wang Jia-Kui Ren Yi-Xun Su Teng Yang Jia-Bo Li Wen-Hui He Peng-Jiao Ma Man-Tian Mi Shuang-Shuang Dai Department of Biochemistry and molecular Biology School of Basic MedicineArmy Medical UniversityChongqing 400038China Research Center for Nutrition and Food Safety Chongqing Key Laboratory of Nutrition and HealthInstitute of Military Preventive MedicineArmy Medical UniversityChongqing 400038China Department of Neurosurgery Daping HospitalArmy Medical UniversityChongqing 400042China Department of Trauma and Emergency Southwest HospitalArmy Medical UniversityChongqing 400038China Department of Histology and Embryology Chongqing Key Laboratory of NeurobiologyBrain and Intelligence Research Key Suyixun Laboratory of Chongqing Education CommissionArmy Medical UniversityChongqing 400038China Research Center Seventh Affiliated Hospital of Sun Yat-Sen UniversityShenzhen 518107GuangdongChina

Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly ***:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral *** also characterized the underlying mechanisms both invitro and invivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout ***:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse *** of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced *** the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high *** the chronic stage,the“FOXO1-transferrin receptor(TFRC)”mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression afte

关键词： Traumatic brain injury(TBI) Neutrophil Forkhead box protein O1(FOXO1) Acute stage Chronic stage

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The next decade of SET:from an oncoprotein to beyond

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Journal of molecular Cell Biology 2024年第1期16卷 1-14页

作者： Han Yao Meng Zhang Donglai Wang State key laboratory of Common Mechanism Research for Major Diseases&Department of Medical genetics Institute of Basic Medical Sciences&School of Basic MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China

This year marks the fourth decade of research into the protein SET,which was discovered in *** was initially identified as an oncoprotein but later shown to be a multifaceted protein involved in regulating numerous biological processes under both physiological and pathophysiological *** dysfunction is closely associated with diseases,such as cancer and Alzheimer's *** the increasing understanding of how SET works and how it is regulated in cells,targeting aberrant SET has emerged as a potential strategy for disease *** this review,we present a comprehensive overview of the advancements in SET studies,encompassing its biological functions,regulatory networks,clinical implications,and pharmacological ***,we provide insights into the future prospects of SET research,with a particular emphasis on its promising potential in the realm of immune modulation.

关键词： SET biological process regulatory mechanism disease therapy

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Multiomics analyses of two Leonurus species illuminate leonurine biosynthesis and its evolution

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molecular Plant 2024年第1期17卷 158-177页

作者： Peng Li Meng-Xiao Yan Pan Liu Dan-Jie Yang Ze-Kun He Yun Gao Yan Jiang Yu Kong Xin Zhong Sheng Wu Jun Yang Hong-Xia Wang Yan-Bo Huang Le Wang Xiao-Ya Chen Yong-Hong Hu Qing Zhao Ping Xu shanghai key laboratory of Plant Functional Genomics and Resources Shanghai Chenshan Botanical GardenShanghai Chenshan Plant Science Research CenterChineseAcademy of SciencesShanghaiChina College of Life Sciences Shanghai Normal UniversityShanghai 200234China State key laboratory of Plant molecular genetics CAS Center for Excellence in Molecular Plant SciencesChinese Academy of SciencesShanghaiChina University of the Chinese Academy of Sciences Beijing 100049China The Research Center of Chiral Drugs Innovation Research Institute of Traditional Chinese MedicineShanghai University of Traditional Chinese Medicine1200 Cailun RoadShanghai 201203China College of Chemistry and Chemical Engineering Shanghai University of Engineering ScienceShanghai 201620China

The Lamiaceae family is renowned for its terpenoid-based medicinal components,but Leonurus,which has traditional medicinal uses,stands out for its alkaloid-rich ***,the principal active compound found in Leonurus,has demonstrated promising effects in reducing blood lipids and treating ***,the biosynthetic pathway of leonurine remains largely ***,we present the chromosome-level genome sequence assemblies of Leonurus japonicus,known for its high leonurine production,and Leonurus sibiricus,characterized by very limited leonurine *** integrating genomics,RNA sequencing,metabolomics,and enzyme activity assay data,we constructed the leonurine biosynthesis pathway and identified the arginine decarboxylase(ADC),uridine diphosphate glucosyltransferase(UGT),and serine carboxypeptidase-like(SCPL)acyltransferase enzymes that catalyze key reactions in this *** analyses revealed that the UGT–SCPL gene cluster evolved by gene duplication in the ancestor of Leonurus and neofunctionalization of SCPL in ***,which contributed to the accumulation of leonurine specifically in ***,our comprehensive study illuminates leonurine biosynthesis and its evolution in Leonurus.

关键词： Lamiaceae Leonurus japonicus Leonurus sibiricus genome sequence alkaloids leonurine gene cluster biosynthetic pathway evolution

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RSPSSL:A novel high-fidelity Raman spectral preprocessing scheme to enhance biomedical applications and chemical resolution visualization

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Light(Science & Applications) 2024年第2期13卷 366-386页

作者： Jiaqi Hu Gina Jinna Chen Chenlong Xue Pei Liang Yanqun Xiang Chuanlun Zhang Xiaokeng Chi Guoying Liu Yanfang Ye Dongyu Cui De Zhang Xiaojun yu Hong Dang Wen Zhang Junfan Chen Quan Tang Penglai Guo Ho-Pui Ho Yuchao Li Longqing Cong Perry Ping Shum State key laboratory of Optical Fiber and Cable Manufacture Technology Guangdong Key Laboratory of Integrated Optoelectronics IntellisenseDepartment of EEESouthern University of Science and TechnologyShenzhen 518055China College of Optical and Electronic Technology China Jiliang UniversityHangzhou 310018China Department of Nasopharyngeal Carcinoma Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangzhou 510060China Department of Ocean Science and Engineering Southern University of Science and TechnologyShenzhen 518055China Department of Nephrology Chaozhou People’s HospitalChaozhou 521011China Clinical Research Design Division Sun Yatsen Memorial HospitalGuangzhouGuangdong 510120China School of Automation Northwestern Polytechnical UniversityXi’anShaanxi 710072China Department of Biomedical Engineering The Chinese University of Hong KongHong KongChina Guangdong Provincial key laboratory of Nanophotonic Manipulation Institute of NanophotonicsJinan UniversityGuangzhou 511443China

Raman spectroscopy has tremendous potential for material analysis with its molecular fingerprinting capability in many branches of science and *** is also an emerging omics technique for metabolic profiling to shape precision ***,precisely attributing vibration peaks coupled with specific environmental,instrumental,and specimen noise is *** Raman spectral preprocessing to remove statistical bias noise and sample-related errors should provide a powerful tool for valuable information ***,we propose a novel Raman spectral preprocessing scheme based on self-supervised learning(RSPSSL)with high capacity and spectral *** can preprocess arbitrary Raman spectra without further training at a speed of~1900 spectra per second without human *** experimental data preprocessing trial demonstrated its excellent capacity and signal fidelity with an 88%reduction in root mean square error and a 60%reduction in infinite norm(L__(∞))compared to established *** this advantage,it remarkably enhanced various biomedical applications with a 400%accuracy elevation(ΔAUC)in cancer diagnosis,an average 38%(few-shot)and 242%accuracy improvement in paraquat concentration prediction,and unsealed the chemical resolution of biomedical hyperspectral images,especially in the spectral fingerprint *** precisely preprocessed various Raman spectra from different spectroscopy devices,laboratories,and diverse *** scheme will enable biomedical mechanism screening with the label-free volumetric molecular imaging tool on organism and disease metabolomics profiling with a scenario of high throughput,cross-device,various analyte complexity,and diverse applications.

关键词： spectral scheme resolution

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