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Mapping Multi-factor-mediated chromatin interactions to Assess Dysregulation of Lung Cancer-related Genes

Genomics, Proteomics & Bioinformatics 2023年第3期21卷 573-588页

作者： Yan Zhang Jingwen Zhang Wei Zhang Mohan Wang Shuangqi Wang Yao Xu Lun Zhao Xingwang Li Guoliang Li National Key Laboratory of Crop Genetic Improvement Huazhong Agricultural UniversityWuhan 430070China Hubei Key Laboratory of Agricultural Bioinformatics and Hubei Engineering Technology Research Center of Agricultural Big Data 3D Genomics Research CenterHuazhong Agricultural UniversityWuhan 430070China

Studies on the lung cancer genome are indispensable for developing a cure for lung ***-genome resequencing,genome-wide association studies,and transcriptome sequencing have greatly improved our understanding of the cancer ***,dysregulation of longrange chromatin interactions in lung cancer remains poorly *** better understand the three-dimensional(3D)genomic interaction features of the lung cancer genome,we used the A549 cell line as a model system and generated high-resolution chromatin interactions associated with RNA polymerase II(RNAPII),CCCTC-binding factor(CTCF),enhancer of zeste homolog 2(EZH2),and histone 3 lysine 27 trimethylation(H3K27me3)using long-read chromatin interaction analysis by paired-end tag sequencing(ChIA-PET).Analysis showed that EZH2/H3K27me3-mediated interactions further repressed target genes,either through loops or domains,and their distributions along the genome were distinct from and complementary to those associated with ***-related genes were highly enriched with chromatin interactions,and chromatin interactions specific to the A549 cell line were associated with oncogenes and tumor suppressor genes,such as additional repressive interactions on FOXO4 and promoter–promoter interactions between NF1 and *** of an anchor associated with chromatin interactions reversed the dysregulation of cancer-related genes,suggesting that chromatin interactions are essential for proper expression of lung cancer-related *** findings demonstrate the 3D landscape and gene regulatory relationships of the lung cancer genome.

关键词： Lung cancer 3D genome ChIA-PET chromatin interaction Dysregulation

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Tn5-FISH,a novel cytogenetic method to image chromatin interactions with sub-kilobase resolution

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Journal of Genetics and Genomics 2020年第12期47卷 727-734页

作者： Jing Niu Xu Zhang Li Guipeng Pixi Yan Qing Yan Qionghai Dai Dayong Jin Xiaohua Shen Jichang Wang Michael QZhang Juntao Gao School of Medicine Tsinghua UniversityBeijing 100084China Department of Automation Tsinghua UniversityBeijing 100084China Beijing Institute of Collaborative Innovation Beijing 100094China Medi-X Institute SUSTech Academy for Advanced Interdisciplinary StudiesSouthern University of Science and TechnologyShenzhen 518055China Department of Biology Southern University of Science and TechnologyShenzhen 518055China MOE Key Laboratory of Bioinformatics Bioinformatics DivisionBNRistCenter for Synthetic&Systems BiologyTsinghua UniversityBeijing 100084China Institute for Biomedical Materials and Devices(IBMD) Faculty of ScienceUniversity of Technology SydneyNSW 2007Australia UTS-SUStech Joint Research Centre for Biomedical Materials and Devices Department of Biomedical EngineeringSouthern University of Science and TechnologyShenzhen 518055China Key Laboratory for Stem Cells and Tissue Engineering(Sun Yat-sen University) Ministry of EducationGuangzhou 510080China Department of histology and embryology Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China Department of Biological Sciences Center for Systems BiologyThe University of TexasDallasTX 75080-3021USA

There is an increasing interest in understanding how three-dimensional(3D)organization of the genome is *** strategies have been employed to identify genome-wide chromatin ***,due to current limitations in resolving genomic contacts,visualization and validation of these genomic loci with sub-kilobase resolution remain unsolved to ***,we describe Tn5 transposase-based Fluorescencein situhybridization(Tn5-FISH),a PCR-based,cost-effective imaging method,which can co-localize the genomic loci with sub-kilobase resolution,dissect genome architecture,and verify chromatin interactions detected by chromatin configuration capture(3C)-derived *** validate this method,short-range interactions in keratin-encoding gene(KRT)locus in topologically associated domain(TAD)were imaged by triple-color Tn5-FISH,indicating that Tn5-FISH is very useful to verify short-range chromatin interactions inside the contact domain and ***,Tn5-FISH can be a powerful molecular tool for the clinical detection of cytogenetic changes in numerous genetic diseases such as cancers.

关键词： Fluorescencein situhybridization chromatin interaction Cellular imaging Super resolution

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Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

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Protein & Cell 2016年第4期7卷 250-266页

作者： Zhuoya Gu Ke Jin M. James C. Crabbe Yang Zhang Xiaolin Liu Yanyan Huang Mengyi Hua Peng Nan Zhaolei Zhang Yang Zhong School of Life Sciences Fudan University Shanghai 200433 China Banting and Best Department of Medical Research DonneUy Centre University of Toronto Toronto ON M5S 1A1 Canada Department of Zoology University of Oxford Tinbergen Building South Parks Road Oxford OXl 3PS UK Institute of Biomedical and Environmental Science & Technology Department of Life Sciences University of Bedfordshire Park Square Luton LU1 3JU UK Department of Bioengineering University of Illinois at Urbana-Champaign Champaign IL 61801 USA School of Public Health University of Michigan Ann Arbor MI 48109 USA Department of Molecular Genetics University of Toronto Toronto ON M5S 1A1 Canada Institute of Biodiversity Science and Institute of High Altitude Medicine Tibet University Lhasa 850012 China

Transposable elements （TEs） have no longer been totally considered as ＂junk DNA＂ for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Tech- nologies based on 3C （chromosome conformation capture） have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions （hESC： r= 0.9, P〈 2.2 × 10^16; IMRg0 fibroblasts： r= 0.94, P 〈 2.2 ×10^16） and also have asignificant positive correlation with some remote functional DNA elements like enhancers and promoters （Enhancer： hESC： r= 0.997, P= 2.3× 10^-4; IMR90： r- 0.934, P= 2 × 10^-2; Promoter： hESC： r= 0.995, P= 3.8 × 10^-4; IMR90： r= 0.996, P = 3.2 × 10^-4）. Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes.

关键词： chromatin interaction alternativeparameter of Hi-C data open chromatin methylationpotential

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Evidence of constraint in the 3D genome for trans-splicing in human cells

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Science China(Life Sciences) 2020年第9期63卷 1380-1393页

作者： Cong Liu Yiqun Zhang Xiaoli Li Yan Jia Feifei Li Jing Li Zhihua Zhang CAS Key Laboratory of Genome Sciences and Information Beijing Institute of Genomicsand China National Center for BioinformationChinese Academy of SciencesBeijing 100101China School of Life Science University of Chinese Academy of SciencesBeijing 100049China

Fusion transcripts are commonly found in eukaryotes, and many aberrant fusions are associated with severe diseases, including cancer. One class of fusion transcripts is generated by joining separate transcripts through trans-splicing. However, the mechanism of trans-splicing in mammals remains largely elusive. Here we showed evidence to support an intuitive hypothesis that attributes trans-splicing to the spatial proximity between premature transcripts. A novel trans-splicing detection tool(TSD) was developed to reliably identify intra-chromosomal trans-splicing events(i TSEs) from RNA-seq data. TSD can maintain a remarkable balance between sensitivity and accuracy, thus distinguishing it from most state-of-the-art tools. The accuracy of TSD was experimentally demonstrated by excluding potential false discovery from mosaic genome or template switching during PCR. We showed that i TSEs identified by TSD were frequently found between genomic regulatory elements, which are known to be more prone to interact with each other. Moreover, i TSE sites may be more physically adjacent to each other than random control in the tested human lymphoblastoid cell line according to Hi-C data. Our results suggest that trans-splicing and 3 D genome architecture may be coupled in mammals and that our pipeline, TSD, may facilitate investigations of trans-splicing on a systematic and accurate level previously thought impossible.

关键词： trans-splicing chromatin interaction 3D genome spatial clustering

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GITAR: An Open Source Tool for Analysis and Visualization of Hi-C Data

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Genomics, Proteomics & Bioinformatics 2018年第5期16卷 365-372页

作者： Riccardo Calandrelli Qiuyang Wu Jihong Guan Sheng Zhong Department of Bioengineering University of California San Diego Department of Computer Science and Technology Tongji University

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 *** 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://*** as an open-source software.

关键词： chromatin interaction Pipeline Hi-C data normalization Topologically-associated domain Processed Hi-C data library

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(Tn5-)FISH-based imaging in the era of 3D/spatial genomics

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Biophysics Reports 2023年第1期9卷 15-25页

作者： Liheng Yang Yan Yan Jun Lin Li Cheng Zhou Jinlan Jin Tongmei Zhang Haokaifeng Wu Xingang Li Wei Wang Li Yuan Xu Zhang Juntao Gao Seaver College Pepperdine University Center for Synthetic & Systems Biology Tsinghua University 3. Bioinformatics Division BNRist Department of Automation MOE Key Laboratory of Bioinformatics Savaid Medical School University of Chinese Academy of Sciences Department of Radiation Oncology Nanfang Hospital Southern Medical University Department of Critical Care Medicine Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine 8. Medical Oncology Beijing Chest Hospital Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute Centre for Regenerative Medicine and Health Hong Kong Institute of Science & Innovation Chinese Academy of Sciences Key Laboratory of Biological Targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital of Guangzhou Medical University Centre for Precision Health Edith Cowan University Beijing Institute of Collaborative Innovation Institute for TCM-X

3D genomics mainly focuses on the 3D position of single genes at the cell level, while spatial genomics focuses more on the tissue level. In this exciting new era of 3D/spatial genomics, half-century old FISH and its derivative methods, including Tn5-FISH, play important roles. In this review, we introduce the Tn5-FISH we developed recently, and present six different applications published by our collaborators and us, based on(Tn5-)FISH, which can be either general BAC clone-based FISH or Tn5-FISH. In these interesting cases,(Tn5-)FISH demonstrated its vigorous ability of targeting sub-chromosomal structures across different diseases and cell lines(leukemia, m ESCs(mouse embryonic stem cells), and differentiation cell lines). Serving as an effective tool to image genomic structures at the kilobase level,Tn5-FISH holds great potential to detect chromosomal structures in a high-throughput manner, thus bringing the dawn for new discoveries in the great era of 3D/spatial genomics.

关键词： Molecular imaging Tn5-FISH chromatin interaction Regulatory elements

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Understanding spatial organizations of chromosomes via statistical analysis of Hi-C data

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Frontiers of Electrical and Electronic Engineering in China 2013年第2期8卷 156-174页

作者： Ming Hu Ke Deng Zhaohui Qin Jun S. Liu Department of Statistics Harvard University Cambridge MA 02138 USA Mathematical Sciences Center Tsinghua University Beijing 100084 China Department of Biostatistics and Bioinformatics Rollins School of Public Health Emory University Atlanta GA 30322 USA

Understanding how chromosomes fold provides insights into the transcription regulation, hence, the functional state of the cell. Using the next generation sequencing technology, the recently developed Hi-C approach enables a global view of spatial chromatin organization in the nucleus, which substantially expands our knowledge about genome organization and function. However, due to multiple layers of biases, noises and uncertainties buried in the protocol of Hi-C experiments, analyzing and interpreting Hi- C data poses great challenges, and requires novel statistical methods to be developed. This article provides an overview of recent Hi-C studies and their impacts on biomedical research, describes major challenges in statistical analysis of Hi-C data, and discusses some perspectives for future research.

关键词： Polymer Model chromatin interaction Topological Domain Chromosome Conformation Capture Biophysical Principle

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Screening and functional analysis of the long-range interaction elements ofβ-globin genes

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Journal of Hainan Medical University 2022年第24期28卷 1-7页

作者： XIAO Yi-shu XU Lan LIU Chun-ya DU Le SUN Yuan-tian LI Dong-na REN Li-cheng Department of Biology Hainan Medical UniversityHaikou 571199China

Objective:Studies have shown thatβ-globin gene presents a selective expression transformation mechanism during development,and its upstream locus control region(LCR)regulates the expression pattern ofβ-globin gene *** further explore the molecular network ofβ-globin gene expression regulation,other long-range regulatory elements that may be involved in the regulation ofβ-globin gene expression were screened and the dynamic regulation and transformation mechanism ofβ-globin gene was deeply ***:Promyelocytic cells were induced to differentiate by all-trans retinoic acid.β-globin gene promoter region and LCR were used as the target sites for circular chromosome conformational capture(4C)*** sequencing and regulatory element analysis,the sites interacting withβ-globin family loci were screened in the whole ***:According to the results of 4C sequencing,the sites that interact with HBD promoter region and LCR were *** by chromosome conformational capture(3C),the results were consistent with those of *** functional analysis of regulatory elements by formaldehyde-assisted separation regulatory elements and Epiregio online website showed that the screening sites AC105129.4,AL354707.17,AC078785.22 and AC021646.35 were all potential regulatory elements involved inβ-globin ***:The interaction between 4C screening site and anchor site showed the complex spatial organization ofβ-globin family loci in the nucleus.

关键词： β-Globin gene Circular chromosome conformation capture chromatin interaction Chromosome conformation capture

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Meeting report on RECOMB 2013 （the 17th Annual International Conference on Research in Computational Molecular Biology）

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Frontiers of Electrical and Electronic Engineering in China 2013年第2期8卷 175-181页

作者： Xuegong Zhang Fengzhu Sun MOE Key Laboratory of Bioinformatics and Bioinformatics Division/Center for Synthetic and Systems Biology TNLIST and Department of Automation Tsinghua University Beijing 100084 China Molecular and Computational Biology Program University of Southern California Los Angeles CA 90089 USA

RECOMB 2013 was successfully held in Tsinghua University, Beijing, China on April 7-10, 2013, hosted by the Bioinformatics Division and Center for Synthetic and Systems Biology, Tsinghua National Laboratory for Information Science and Technology （TNLIST）. A total of about 500 professionals from both academia and industry from 29 countries and regions attended the conference and its RECOMB-Seq satellite workshop after the main conference.

关键词： Residual Dipolar Coupling chromatin interaction Keynote Speaker Pedigree Reconstruction Computational Molecular Biology

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