Topologically associating domain(TAD)reorganization commonly occurs in the cell nucleus and contributes to gene activation and inhibition through the separation or fusion of adjacent TADs.However,functional genes impa...Topologically associating domain(TAD)reorganization commonly occurs in the cell nucleus and contributes to gene activation and inhibition through the separation or fusion of adjacent TADs.However,functional genes impacted by TAD alteration and the underlying mechanism of TAD reorganization regulating gene transcription remain to be fully elucidated.Here,we first developed a novel approach termed Inter3D to specifically identify genes regulated by TAD reorganization.Our study revealed that the segregation of TADs led to the disruption of intrachromosomal looping at the myosin light chain 12B(MYL12B)locus,via the meticulous reorganization of TADs mediating epigenomic landscapes within tumor cells,thereby exhibiting a significant correlation with the down-regulation of its transcriptional activity.Conversely,the fusion of TADs facilitated intrachromosomal interactions,suggesting a potential association with the activation of cytochrome P450 family 27 subfamily B member 1(CYP27B1).Our study provides comprehensive insight into the capture of TAD rearrangement-mediated gene loci and moves toward understanding the functional role of TAD reorganization in gene transcription.The Inter3D pipeline developed in this study is freely available at https://github.com/bm2-lab/inter3D and https://ngdc.cncb.ac.cn/biocode/tool/BT7399.展开更多
Recent advances in high-throughput chromosome conformation capture(Hi-C)techniques have allowed us to map genome-wide chromatin interactions and uncover higher-order chromatin structures,thereby shedding light on the ...Recent advances in high-throughput chromosome conformation capture(Hi-C)techniques have allowed us to map genome-wide chromatin interactions and uncover higher-order chromatin structures,thereby shedding light on the principles of genome architecture and functions.However,statistical methods for detecting changes in large-scale chromatin organization such as topologically associating domains(TADs)are still lacking.Here,we proposed a new statistical method,DiffGR,for detecting differentially interacting genomic regions at the TAD level between Hi-C contact maps.We utilized the stratum-adjusted correlation coefficient to measure similarity of local TAD regions.We then developed a nonparametric approach to identify statistically significant changes of genomic interacting regions.Through simulation studies,we demonstrated that DiffGR can robustly and effectively discover differential genomic regions under various conditions.Furthermore,we successfully revealed cell type-specific changes in genomic interacting regions in both human and mouse Hi-C datasets,and illustrated that DiffGR yielded consistent and advantageous results compared with state-of-the-art differential TAD detection methods.The DiffGR R package is published under the GNU General Public License(GPL)≥2 license and is publicly available at https://github.com/wmalab/DiffGR.展开更多
The immune checkpoint blockade(ICB)targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers.However,the low response rate and frequently observed severe side effects limit its broad benefits.It is part...The immune checkpoint blockade(ICB)targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers.However,the low response rate and frequently observed severe side effects limit its broad benefits.It is partially due to less understanding of the biological regulation of PD-L1.Here,we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation.In PD-L1 and PD-L2 highly expressed cancer cells,a new TAD(topologically associating domain)(chr9:5,400,000-5,600,000)around CD274 and CD273 was discovered,which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2.The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1.After transcription,the PD-L1 is tightly regulated by mi RNAs and RNA-binding proteins via the long 3’UTR.At translational level,PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination.In addition,PD-L1 can be secreted via exosome to systematically inhibit immune response.Therefore,fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.展开更多
Background:The hierarchical three-dimensional(3D)architectures of chromatin play an important role in fundamental biological processes,such as cell differentiation,cellular senescence,and transcriptional regulation.Ab...Background:The hierarchical three-dimensional(3D)architectures of chromatin play an important role in fundamental biological processes,such as cell differentiation,cellular senescence,and transcriptional regulation.Aberrant chromatin 3D structural alterations often present in human diseases and even cancers,but their underlying mechanisms remain unclear.Results:3D chromatin structures(chromatin compartment A/B,topologically associated domains,and enhancerpromoter interactions)play key roles in cancer development,metastasis,and drug resistance.Bioinformatics techniques based on machine learning and deep learning have shown great potential in the study of 3D cancer genome.Conclusion:Current advances in the study of the 3D cancer genome have expanded our understanding of the mechanisms underlying tumorigenesis and development.It will provide new insights into precise diagnosis and personalized treatment for cancers.展开更多
The three-dimensional(3D)conformation of chromatin is integral to the precise regulation of gene expression.The 3D genome and genomic variations in non-alcoholic fatty liver disease(NAFLD)are largely unknown,despite t...The three-dimensional(3D)conformation of chromatin is integral to the precise regulation of gene expression.The 3D genome and genomic variations in non-alcoholic fatty liver disease(NAFLD)are largely unknown,despite their key roles in cellular function and physiological processes.Highthroughput chromosome conformation capture(Hi-C),Nanopore sequencing,and RNA-sequencing(RNA-seq)assays were performed on the liver of normal and NAFLD mice.A high-resolution 3D chromatin interaction map was generated to examine different 3D genome hierarchies including A/B compartments,topologically associated domains(TADs),and chromatin loops by Hi-C,and whole genome sequencing identifying structural variations(SVs)and copy number variations(CNVs)by Nanopore sequencing.We identified variations in thousands of regions across the genome with respect to 3D chromatin organization and genomic rearrangements,between normal and NAFLD mice,and revealed gene dysregulation frequently accompanied by these variations.Candidate target genes were identified in NAFLD,impacted by genetic rearrangements and spatial organization disruption.Our data provide a high-resolution 3D genome interaction resource for NAFLD investigations,revealed the relationship among genetic rearrangements,spatial organization disruption,and gene regulation,and identified candidate genes associated with these variations implicated in the pathogenesis of NAFLD.The newly findings offer insights into novel mechanisms of NAFLD pathogenesis and can provide a new conceptual framework for NAFLD therapy.展开更多
Interactions between chromatin segments play a large role in functional genomic assays and developments in genomic interaction detection methods have shown interacting topological domains within the genome. Among thes...Interactions between chromatin segments play a large role in functional genomic assays and developments in genomic interaction detection methods have shown interacting topological domains within the genome. Among these methods, Hi-C plays a key role. Here, we present the Genome Interaction Tools and Resources(GITAR), a software to perform a comprehensive Hi-C data analysis, including data preprocessing, normalization, and visualization, as well as analysis of topologically-associated domains(TADs). GITAR is composed of two main modules:(1)HiCtool, a Python library to process and visualize Hi-C data, including TAD analysis; and(2)processed data library, a large collection of human and mouse datasets processed using HiCtool.HiCtool leads the user step-by-step through a pipeline, which goes from the raw Hi-C data to the computation, visualization, and optimized storage of intra-chromosomal contact matrices and TAD coordinates. A large collection of standardized processed data allows the users to compare different datasets in a consistent way, while saving time to obtain data for visualization or additional analyses. More importantly, GITAR enables users without any programming or bioinformatic expertise to work with Hi-C data. GITAR is publicly available at http://genomegitar.org as an open-source software.展开更多
The expression of linear DNA sequence is precisely regulated by the three-dimensional(3D)architecture of chromatin.Morphine-induced aberrant gene networks of neurons have been extensively investigated;however,how morp...The expression of linear DNA sequence is precisely regulated by the three-dimensional(3D)architecture of chromatin.Morphine-induced aberrant gene networks of neurons have been extensively investigated;however,how morphine impacts the 3D genomic architecture of neurons is still unknown.Here,we applied digestion-ligation-only high-throughput chromosome conformation capture(DLO Hi-C)technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons.After receiving continuous morphine administration for 90 days on rhesus monkeys,we discovered that morphine re-arranged chromosome territories,with a total of 391 segmented compartments being switched.Morphine altered over half of the detected topologically associated domains(TADs),most of which exhibited a variety of shifts,followed by separating and fusing types.Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops.Moreover,all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops,and were further validated for changed expression.Collectively,an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects.Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82372705 and 31870748)the Shanghai Oriental Elite Project(Grant No.2000152009)+7 种基金the National Key R&D Program of China(Grant No.2017YFE0196300)the Shanghai Natural Science Foundation(Grant No.22ZR1466100)the Fundamental Research Funds for the Central Universities(Grant No.22120230292)the China Postdoctoral Science Foundation(Grant Nos.2023M742651 and GZC20231946)the Shuguang Project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation(Grant No.17SG19)the Outstanding Yong Medical Scholar of Shanghai Municipal Commission of Health and Family Planning(Grant No.2017YQ067)the Outstanding Yong Scholar Grant of Tongji University(Grant No.PA2019000239)the Startup Funding of Frontier Science Research Center for Stem Cells&Shanghai East Hospital of Tongji University(Grant No.DFRC2019003),China.
文摘Topologically associating domain(TAD)reorganization commonly occurs in the cell nucleus and contributes to gene activation and inhibition through the separation or fusion of adjacent TADs.However,functional genes impacted by TAD alteration and the underlying mechanism of TAD reorganization regulating gene transcription remain to be fully elucidated.Here,we first developed a novel approach termed Inter3D to specifically identify genes regulated by TAD reorganization.Our study revealed that the segregation of TADs led to the disruption of intrachromosomal looping at the myosin light chain 12B(MYL12B)locus,via the meticulous reorganization of TADs mediating epigenomic landscapes within tumor cells,thereby exhibiting a significant correlation with the down-regulation of its transcriptional activity.Conversely,the fusion of TADs facilitated intrachromosomal interactions,suggesting a potential association with the activation of cytochrome P450 family 27 subfamily B member 1(CYP27B1).Our study provides comprehensive insight into the capture of TAD rearrangement-mediated gene loci and moves toward understanding the functional role of TAD reorganization in gene transcription.The Inter3D pipeline developed in this study is freely available at https://github.com/bm2-lab/inter3D and https://ngdc.cncb.ac.cn/biocode/tool/BT7399.
基金supported by the National Science Foundation,USA(Grant No.DBI-1751317)the National Institute of Health,USA(Grant No.R35GM133678).
文摘Recent advances in high-throughput chromosome conformation capture(Hi-C)techniques have allowed us to map genome-wide chromatin interactions and uncover higher-order chromatin structures,thereby shedding light on the principles of genome architecture and functions.However,statistical methods for detecting changes in large-scale chromatin organization such as topologically associating domains(TADs)are still lacking.Here,we proposed a new statistical method,DiffGR,for detecting differentially interacting genomic regions at the TAD level between Hi-C contact maps.We utilized the stratum-adjusted correlation coefficient to measure similarity of local TAD regions.We then developed a nonparametric approach to identify statistically significant changes of genomic interacting regions.Through simulation studies,we demonstrated that DiffGR can robustly and effectively discover differential genomic regions under various conditions.Furthermore,we successfully revealed cell type-specific changes in genomic interacting regions in both human and mouse Hi-C datasets,and illustrated that DiffGR yielded consistent and advantageous results compared with state-of-the-art differential TAD detection methods.The DiffGR R package is published under the GNU General Public License(GPL)≥2 license and is publicly available at https://github.com/wmalab/DiffGR.
基金supported by the National Natural Science Foundation of China(3197061631770935+2 种基金81873531and 82070505)the Distinguished Professorship Program of Jiangsu Province to Yihui Fan,the Distinguished Professorship Program of Jiangsu Province to Renfang Mao,The National Undergraduate Training Programs for Innovation(202010304109Y,China)。
文摘The immune checkpoint blockade(ICB)targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers.However,the low response rate and frequently observed severe side effects limit its broad benefits.It is partially due to less understanding of the biological regulation of PD-L1.Here,we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation.In PD-L1 and PD-L2 highly expressed cancer cells,a new TAD(topologically associating domain)(chr9:5,400,000-5,600,000)around CD274 and CD273 was discovered,which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2.The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1.After transcription,the PD-L1 is tightly regulated by mi RNAs and RNA-binding proteins via the long 3’UTR.At translational level,PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination.In addition,PD-L1 can be secreted via exosome to systematically inhibit immune response.Therefore,fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.
基金supported by the Beijing Nova Program of Science and Technology(No.20220484198 to HC)the National Natural Science Foundation of China(Nos.62173338,61873276 and 31900488 to HC,XB,and HL,respectively).
文摘Background:The hierarchical three-dimensional(3D)architectures of chromatin play an important role in fundamental biological processes,such as cell differentiation,cellular senescence,and transcriptional regulation.Aberrant chromatin 3D structural alterations often present in human diseases and even cancers,but their underlying mechanisms remain unclear.Results:3D chromatin structures(chromatin compartment A/B,topologically associated domains,and enhancerpromoter interactions)play key roles in cancer development,metastasis,and drug resistance.Bioinformatics techniques based on machine learning and deep learning have shown great potential in the study of 3D cancer genome.Conclusion:Current advances in the study of the 3D cancer genome have expanded our understanding of the mechanisms underlying tumorigenesis and development.It will provide new insights into precise diagnosis and personalized treatment for cancers.
基金financially supported by Liao Ning Revitalization Talents Program(XLYC1802121,China)。
文摘The three-dimensional(3D)conformation of chromatin is integral to the precise regulation of gene expression.The 3D genome and genomic variations in non-alcoholic fatty liver disease(NAFLD)are largely unknown,despite their key roles in cellular function and physiological processes.Highthroughput chromosome conformation capture(Hi-C),Nanopore sequencing,and RNA-sequencing(RNA-seq)assays were performed on the liver of normal and NAFLD mice.A high-resolution 3D chromatin interaction map was generated to examine different 3D genome hierarchies including A/B compartments,topologically associated domains(TADs),and chromatin loops by Hi-C,and whole genome sequencing identifying structural variations(SVs)and copy number variations(CNVs)by Nanopore sequencing.We identified variations in thousands of regions across the genome with respect to 3D chromatin organization and genomic rearrangements,between normal and NAFLD mice,and revealed gene dysregulation frequently accompanied by these variations.Candidate target genes were identified in NAFLD,impacted by genetic rearrangements and spatial organization disruption.Our data provide a high-resolution 3D genome interaction resource for NAFLD investigations,revealed the relationship among genetic rearrangements,spatial organization disruption,and gene regulation,and identified candidate genes associated with these variations implicated in the pathogenesis of NAFLD.The newly findings offer insights into novel mechanisms of NAFLD pathogenesis and can provide a new conceptual framework for NAFLD therapy.
基金supported by the National Institutes of Health,United States(Grant Nos.U01CA200147 and DP1HD087990)awarded to SZ
文摘Interactions between chromatin segments play a large role in functional genomic assays and developments in genomic interaction detection methods have shown interacting topological domains within the genome. Among these methods, Hi-C plays a key role. Here, we present the Genome Interaction Tools and Resources(GITAR), a software to perform a comprehensive Hi-C data analysis, including data preprocessing, normalization, and visualization, as well as analysis of topologically-associated domains(TADs). GITAR is composed of two main modules:(1)HiCtool, a Python library to process and visualize Hi-C data, including TAD analysis; and(2)processed data library, a large collection of human and mouse datasets processed using HiCtool.HiCtool leads the user step-by-step through a pipeline, which goes from the raw Hi-C data to the computation, visualization, and optimized storage of intra-chromosomal contact matrices and TAD coordinates. A large collection of standardized processed data allows the users to compare different datasets in a consistent way, while saving time to obtain data for visualization or additional analyses. More importantly, GITAR enables users without any programming or bioinformatic expertise to work with Hi-C data. GITAR is publicly available at http://genomegitar.org as an open-source software.
基金supported by the grants from the National Natural Science Foundation of China(Grant Nos.82071494,81871043,32000719,and 81272459)the 1.3.5 Project for Disciplines of Excellence of West China Hospital of Sichuan University(Grant No.ZYGD23011)+3 种基金the China Postdoctoral Science Foundation(Grant No.2021M702362)the PostDoctor Research Project,West China Hospital,Sichuan University(Grant No.2020HXBH010)the Sichuan Science and Technology Program(Grant No.23NSFSC2884)the Science,Technology and Innovation Commission of Shenzhen Municipality(Grant No.ZDSYS20190902093601675),China.
文摘The expression of linear DNA sequence is precisely regulated by the three-dimensional(3D)architecture of chromatin.Morphine-induced aberrant gene networks of neurons have been extensively investigated;however,how morphine impacts the 3D genomic architecture of neurons is still unknown.Here,we applied digestion-ligation-only high-throughput chromosome conformation capture(DLO Hi-C)technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons.After receiving continuous morphine administration for 90 days on rhesus monkeys,we discovered that morphine re-arranged chromosome territories,with a total of 391 segmented compartments being switched.Morphine altered over half of the detected topologically associated domains(TADs),most of which exhibited a variety of shifts,followed by separating and fusing types.Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops.Moreover,all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops,and were further validated for changed expression.Collectively,an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects.Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.
