Max-Delbrück-Centrum für Molekulare Medizin | MDC · Berlin Institute for Medical Systems Biology
报告题目：Specialization of 3D genome structure in different cell types and states
报告摘要：The three-dimensional (3D) structure of chromosomes is associated with gene regulation and cell function. Understanding how 3D genome structure varies between cell types and states, in development and disease, promises to enhance the interpretation of genome sequence variation and to accelerate the discovery of disease target genes. To explore 3D genome structure variation in early development and highly specialized cells in the brain, we applied Genome Architecture Mapping in different cell types from the adult murine brain: oligodendroglia (OLGs) from the cortex, dopaminergic neurons (DNs) from the midbrain and pyramidal glutamatergic neurons (PGNs) from the hippocampus. We found extensive cell-type specialisation of 3D chromatin contacts, such as extensive reorganisation of topological domains (TADs) and eu/heterochromatic compartments. We also discover the large scale decondensation, or ‘melting’, of long genes when most highly expressed, many with roles in neurodevelopmental and neurodegeneration disorders. Through integration of 3D genome structure with single-cell expression and chromatin accessibility, we find that PGN- and DN-specific hubs of contacts containing genes associated with their specialised functions, such as addiction and synaptic plasticity, respectively. Our current work explores how genetic variation associated with disease interferes with 3D genome structure, or the effects of environmental insults on the complex 3D genome structures of brain cells.
导师为张晓彤教授，合作导师为中国医学科学院基础医学研究所陈阳研究员。研究生课题为生物大数据分析、材料基因组和大数据平台搭建研究，在Computational and Structural Biotechnology Journal等学术期刊上发表了4篇论文；CCF B类会议论文1篇，申请专利3项。参与国家重点研发计划“材料基因工程专用数据库和材料大数据技术”、“国家材料基因工程数据汇交与管理服务技术平台”等项目。
报告摘要：本文提出基于多模态神经网络的方法MINE，以探索调控染色质交互作用的空间密度与染色质空间结构变化、基因表达之间的关系。MINE包括MINE-Loop、MINE-density和MINE-Viewer三个模块，其中MINE-Loop通过集成Hi-C、ChIP-seq和ATAC-seq数据，基于神经网络进行Hi-C数据增强，以提高可检测的调控型染色质交互作用的比例，同时减少非调控染色质交互作用产生的噪声。MINE-Density用于计算由MINE-Loop识别的调控染色质交互作用的空间密度（SD-RCI，spatial density of regulatory chromatin interaction）。MINE-Viewer用于可视化染色质三维结构和特定调控因子在空间的密度。基于上述模块，本文探索了HepG2细胞中调控染色质交互作用的空间密度与基因转录状态之间的关系，并定义了四种不同水平的染色质交互作用密度，这些染色质交互作用密度与锚定调控因子密度高的染色质区域（developed hubs）或锚定调控因子密度低的染色质区域（developing hubs）相关。最后，本文将SD-RCI应用于经1，6-己二醇处理或未处理的HeLa细胞系数据，以定量描述染色质结构的变化。结果表明，用1，6-己二醇处理后的染色质结构扩大。综上所述，MINE方法为定量分析不同染色质构象与基因调控之间的关系提供了一种新方式。
郭亚 上海交通大学生命科学技术学院长聘教轨副教授 博士生导师
Ya Guo is currently an associate professor in the School of Life Sciences and Biotechnology at the Shanghai Jiao Tong University. Ya received his PhD in biology from Shanghai Jiao Tong University in 2015 and carried out postdoctoral studies at Shanghai Jiao Tong University and Imperial College London from 2015 to 2019. Ya’s group is interested in understanding fundamental mechanisms of 3D genome organization. His works showed that the relative orientations of CTCF-binding sites could determine the directionality of DNA looping. Ya also observed an unusual form of cohesin-mediated chromatin interactions, chromatin jets, which provide in vivo evidence and insights into the physiological behavior of cohesin-driven loop extrusion in mammalian cells.
报告题目：Analyses of DNA binding affinity and sequence recognition specificity of the human 3D genome architectural protein CTCF
报告摘要：Transcription factor CTCF, as a key 3D genome organizer, directs the establishment of genome-wide chromatin interactions, which has been implied in gene regulation. It has been shown that human genome contains more than 120,000 potential CTCF-binding sites and ~30,000-80,000 CTCF binding peaks can be identified in a typical mammalian cell. However, the mechanism by which CTCF sites are alternatively activated across the genome has not been fully understood and in vitro DNA-binding activity of CTCF has not been systematically investigated yet. In this study, we established a high-through method to measure the relative binding affinity of CTCF proteins to DNA probes comprising potential genomic CTCF targets. We identified ~168,000 CTCF-binding sites using this high-throughput approach and showed that the CTCF-binding affinity of these sites measured in vitro is closely correlated with both the possibility and strength of CTCF occupancy in vivo. A typical high-affinity CTCF site, which preferentially employs non-core-motif to enhance CTCF-binding ability, is frequently bound by CTCF in most cell types and bridges more chromatin contacts. By contrast, weak CTCF-binding sites are frequently occupied by CTCF in active compartment (A compartment), but not in inactive B compartment. Additionally, we developed a pipeline to predict CTCF binding using an AI-based prediction model. Thus, our data indicate that DNA sequence itself plays a central role in defining CTCF genome-wide binding profiles and functions.
海外高层次青年人才计划、深圳市孔雀人才计划B类。主要从事三维基因组结构建立过程及功能、顺式调控元件功能性鉴定及表观遗传特征分析、发育和分化过程中三维结构和调控元件协同控制基因表达的机制，以及基因调控异常和疾病发生机制等领域的研究。以通讯作者和第一作者在Nature Genetics (1)，Molecular Cell (2)，PNAS(2)，Cell (评论)等国际著名杂志发表多篇研究论文和评论。
报告题目：High-throughput Pore-C reveals the single-allele topology polymorphism and cell type-specificity of 3D genome folding
报告摘要：Canonical three-dimensional (3D) genome structures represent the ensemble average of pairwise chromatin interactions but not the single-allele topologies in populations of cells. Recently developed Pore-C can capture multiway chromatin contacts that reflect regional topologies of single chromosomes. By carrying out high-throughput Pore-C, we reveal extensive but regionally restricted clusters of single-allele topologies that aggregate into canonical 3D genome structures in two human cell types. We show that fragments in multi-contact reads generally coexist in the same TAD. In contrast, a concurrent significant proportion of multi-contact reads span multiple compartments of the same chromatin type over megabase distances. Synergistic chromatin looping between multiple sites in multi-contact reads is extremely rare compared to pairwise interactions. Interestingly, the single-allele topology clusters are cell type-specific even inside highly conserved TADs in different types of cells. In summary, HiPore-C enables global characterization of single-allele topologies at an unprecedented depth to reveal elusive genome folding principles.
林达 (Da Lin)
单位：上海交通大学医学院附属第一人民医院临床转化研究院 (Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine)
报告题目：Robust identification of extrachromosomal DNA and genetic variants using multiple genetic abnormality sequencing (MGA-Seq)
报告摘要：Genomic abnormalities, including structural variation (SV), copy number variation (CNV), single-nucleotide polymorphism (SNP), homogenously staining regions (HSR) and extrachromosomal DNA (ecDNA), are strongly associated with cancer, rare diseases and infertility. A robust technology to simultaneously detect these genomic abnormalities is highly desired for clinical diagnosis and basic research. In this study, we developed a simple and cost-effective method – multiple genetic abnormality sequencing (MGA-Seq) – to simultaneously detect SNPs, CNVs, SVs, ecDNA and HSRs in a single tube. This method has been successfully applied in both cancer cell lines and clinical tumour samples and revealed that focal amplification in tumour tissue is substantially heterogeneous. Notably, we delineated the architecture of focal amplification and the ecDNA network by MGA-Seq, which facilitated the exploration of the regulation of gene expression in ecDNA. This method could be extensively applied for diagnosis and may greatly facilitate the investigation of the genomic mechanism for genetic diseases.
李国强 北京大学生物医学前沿创新中心 研究员
报告题目：The versatile roles of DNA Methylation in understanding chromosome organization
报告摘要：While DNA Methylation is a major epigenetic modification that can modulate chromosome states, its role in orchestrating chromosome organization has not been well elucidated. By utilizing the characteristic patterns of DNA Methylation in different cell types, we first developed a multi-omics assay that can simultaneously capture the chromosome conformation and DNA methylome in bulk and in single cells. Methyl-HiC reveals coordinated DNA methylation status between distal genomic segments that are in spatial proximity in the nucleus and delineates heterogeneity of both the chromatin architecture and DNA methylome in a mixed population. We applied Methyl-HiC on mouse embryonic stem cells with Tet triple knock-out (Tet-TKO) and systematically assessed the effects of DNA Methylation on chromosome organization. Globally, upon Tet TKO, we observed decreased compartmentalization, which corresponds to narrowed methylation differences between CGI-rich and CGI-poor domains. We also observed a significant enrichment of hypermethylation regions in TAD boundaries, which correlated with an unexpected increase in TAD insulation. We also found that the hypermethylation of loop anchors could weaken the possibility of loop formation. Taking advantage of the unique single-molecular property of Methyl-HiC that can link distal DNA Methylation information in single DNA molecular, we further showed that homogeneous DNA Methylation status in distal DNA fragments favors spatial interactions. In summary, our work has shown the broad effects of dynamic DNA Methylation on chromosome organization and provides a unique method for the simultaneous characterization of cell-type-specific chromosome organization and epigenome in complex tissues.
Department of Epigenetics, Institute of Biology, University of Hohenheim, Garbenstrasse 30, 70599 Stuttgart, Germany
报告题目：The plant nuclear lamina disassembles to regulate plant genome folding in stress conditions
报告摘要：The nuclear lamina (NL) is a complex network of nuclear lamins and lamin-associated nuclear membrane proteins, which scaffold the nucleus to maintain structural integrity. In Arabidopsis thaliana, Nuclear Matrix Constituent Proteins (NMCPs) are essential components of the NL and are required to maintain the structural integrity of the nucleus and specific perinuclear chromatin anchoring. At a chromosomal level, plant chromatin organization in interphase nuclei displays flexibilities in response to various developmental cues and environmental factors. Temperature stress is one of the common abiotic stresses that trigger global rearrangement of chromatin, demonstrating a tight connection between the structural arrangement of chromatin and its activities. Based on these observations from Arabidopsis, and given the role of AtNMCP genes (CRWN1 and CRWN4) in organizing chromatin positioning at the nuclear periphery, one can expect considerable changes in chromatin-NL interactions when the global chromatin organization patterns are being altered in plants. In this study, we show that plant nuclear lamina disassembles substantially under various stress conditions. By focusing on heat stress, we reveal that chromatin domains, initially tethered to the nuclear envelope, remain largely associated with CRWN1 and become scattered in the inner nuclear space. Via investigating the three-dimensional chromatin contact network, we further reveal that CRWN1 proteins play a structural role, shaping changes in genome folding under heat stress. Also, CRWN1 acts as a negative transcriptional co-regulator to modulate the shift of the plant transcriptome profile in response to heat stress.
实验室致力于表观遗传信息如何遗传和在调控受精之后胚胎发育的作用的研究。刘江的研究证明除了DNA被遗传外，表观遗传信息也可以通过胚子完整地遗传到子代中去（Cell, 2103, 封面文章）。研究结果改变了传统上认为受精后胚胎发育的信息主要是由卵子提供、而精子只携带一套DNA序列的观念。进而揭示了不同的表观遗传信息（包括DNA甲基化、染色体3D结构、染色体开放性）在不同物种中的跨代遗传和重编程规律、分子机制、及对胚胎发育的调控作用（Cell 2014, 2017, 2018; Nature 2019）。近期他在国际上首次建立了使用DNA甲基化来筛选胚胎用于试管婴儿的方法，临床实验结果显示该方法可以大幅度提高了试管婴儿的出生率，并可以降低出生缺陷的比例。
报告题目：The landscape of high order chromatin structure in human brain during development
本科毕业于武汉大学物理学专业，博士毕业于中国科学院高能物理研究所粒子物理与核物理专业。主持国家自然科学基金面上项目1项，入选湖北省高等学校优秀中青年科技创新团队。在Nature Genetics、Molecular Cell、Molecular Biology and Evolution等杂志上发表论文20多篇。研究领域为以典型动植物及重要生物学过程为对象，基于NGS的表观遗传学、三维基因组学和群体遗传学的整合分析和方法开发。
报告题目：Extensive Chromatin Structure-Function Associations Revealed by Accurate 3D Architecture Characterization
报告摘要：A/B compartments are observed in Hi-C data and coincide with eu/hetero-chromatin. However, many genomic regions are ambiguous under A/B compartment scheme. We develop MOSAIC (MOdularity and Singular vAlue decomposition-based Identification of Compartments), an accurate compartmental state detection scheme. MOSAIC reveals that those ambiguous regions segregate into two additional compartmental states, which typically correspond to short genomic regions flanked by long canonical A/B compartments with opposite activities. They are denoted as micro-compartments accordingly. In contrast to the canonical A/B compartments, micro-compartments cover ～30% of the genome and are highly dynamic across cell types. More importantly, distinguishing the micro-compartments underpins accurate characterization of chromatin structure-function relationship. By applying MOSAIC to GM12878 and K562 cells, we identify CD86, ILDR1 and GATA2 which show concordance between gene expression and compartmental states beyond the scheme of A/B compartments. Taken together, MOSAIC uncovers fine-scale and dynamic compartmental states underlying transcriptional regulation and disease.
李永歌 博士研究生 清华大学医学院
报告题目: Sequential-GAM constructs the single-cell geometric 3D genome structure
报告摘要: The geometric three-dimensional structure of the genome is highly correlated with cell specificity and function, but there are currently insufficient methods for constructing it. Sequential-GAM was created to calculate the geometric structure of the diploid genome of mouse embryonic stem cells by sequentially capturing DNA from each cell. On the basis of the constructed structures, we calculated the chromatin hierarchical structure, which included the radial positions of chromosomes, compartments and subcompartments, and genes. In addition, we clustered TADs according to their structural stability in the cell population and investigated the properties of TAD groups with high internal stability.
刘玉婷 博士研究生 北京大学
报告题目：CTCF acts as a cell identity factor via orchestrating regulatory hubswith pioneer transcription factors
报告摘要：Recent studies have demonstrated that the ubiquitously expressed CTCF plays a critical role in regulating the transcription of cell identity genes during development. However, the molecular mechanism through which CTCF controls the expression of cell identity genes is still elusive. Here, we explored the mechanism by which CTCF exerts its specialized functions in lineage specification through integrative analyses for primary hepatocytes, myocytes and B cells of both mouse and human. We found that CTCF shows lineage-specific occupancy which is determined by lineage-specific pioneer TFs, such as MYOD, FOXA and PU.1, in local and distal ways to control cell identity. Locally, pioneer TFs facilitate lineage-specific CTCF occupancy via opening chromatin. Distally, CTCF and pioneer TFs form regulatory hubs to regulate genes that control cell identity. Importantly, this conserved mechanism in mouse and human is experimentally validated using genetic systems of MyoD-null mice and CTCF degron mice during myogenic differentiation. Taken together, our results uncover a general mechanism in which CTCF acts as a cell identity factor to control cell identity genes via orchestrating regulatory hubs with pioneer TFs.
Prof. Moussa Benhanmed Université Paris-Saclay, Fance
Exploring the chromatin-based regulation of enhancer promoter contact and its impact on gene expression in tomato
报告题目：Exploring the chromatin-based regulation of enhancer promoter contact and its impact on gene expression in tomato
报告摘要：brief summary: Epigenetic regulations have become a major focus of research activity in the current post-genomics era, a period in which the complete genome sequence of multiple model organisms is known. Yet the linear conception of the genome has been replaced by a highly complex and dynamic 3-dimensional organization of chromatin within the nucleus (Rodriguez-Granados et al., 2016; Concia et al., 2020 ; Huang et al., 2021) creating new challenges for the understanding of the control of gene expression but also possibilities to modulate these pathways. Major advances have been made regarding the chromatin regulation of biological processes in model species such as Arabidopsis thaliana. However, the extrapolation of these findings to crop species, such as tomato, remains a challenge. Indeed, the role of the 3D chromatin reorganizations in gene regulation, and how promoter-enhancer contacts are established in response to stress as well as the role of TFs in promoter-enhancer contacts remain largely unknown. In this context, my lab explores the chromatin-based regulation of 3D enhancer promoter contacts and how these nuclear reorganizations impact gene expression in tomato.
彭婷 博士研究生 北京大学
报告题目：Mapping Nucleolus-associated Chromatin Interactions Using Nucleolus Hi-C Reveals Pattern of Heterochromatin Interactions
报告摘要：As the largest substructures in the nucleus, nucleoli are the sites of ribosome biogenesis. Increasing evidence indicates that nucleoli play a key role in the organization of 3D genome architecture, but systematic studies of nucleolus-associated chromatin interactions are lacking. Here, we developed a nucleolus Hi-C (nHi-C) experimental technique to enrich nucleolus-associated chromatin interactions. Using the nHi-C experiment, we identified 264 high-confidence NADs (hNADs) that form strong heterochromatin interactions associated with the nucleolus and consist of 24% of the whole genome. Based on the global hNAD inter-chromosomal interactions, we found five nucleolar organizer region (NOR)-bearing chromosomes formed into two clusters that show different interaction patterns, which is concordant with their epigenetic states and gene expression levels. hNADs can be divided into three groups that display distinct cis/trans interaction signals, interaction frequencies associated with nucleoli, distance from the centromeres, and overlap percentage with lamina-associated domains (LADs). Nucleolus disassembly caused by Actinomycin D (ActD) significantly decreases the strength of hNADs and affects compartment/TAD strength genome-wide. In summary, our results provide a global view of heterochromatin interactions organized around nucleoli and demonstrate that nucleoli act as an inactive inter-chromosomal hub to shape both compartments and TADs.
研究方向为三维基因组学，擅长Hi-C及其他组学数据的分析。作为共同第一作者已在Nature Genetics和Communications Biology期刊上发表了两篇论文。目前致力于开发一种Hi-C数据特征的新的鉴定方法。
报告题目：Three-dimensional folding dynamics of the Xenopus tropicalis genome
报告摘要：Animal interphase chromosomes are organized into topologically associating domains (TADs). How TADs are formed is not fully understood. Here, we combined high-throughput chromosome conformation capture and gene silencing to obtain insights into TAD dynamics in Xenopus tropicalis embryos. First, TAD establishment in X. tropicalis is similar to that in mice and flies and does not depend on zygotic genome transcriptional activation. This process is followed by further refinements in active and repressive chromatin compartments and the appearance of loops and stripes. Second, within TADs, higher self-interaction frequencies at one end of the boundary are associated with higher DNA occupancy of the architectural proteins CTCF and Rad21. Third, the chromatin remodeling factor ISWI is required for de novo TAD formation. Finally, TAD structures are variable in different tissues. Our work shows that X. tropicalis is a powerful model for chromosome architecture analysis and suggests that chromatin remodeling plays an essential role in de novo TAD establishment.
华盛顿大学医学院Sanford C. and Karen P. Loewentheil讲席教授
王艇教授在表观遗传学，转座子，及基因组大数据整合领域是公认的关键意见领袖，王艇教授的主要工作是研究转座子在基因和表观基因层面对基因调控网络的影响，包括他们的组织形态，进化方式，及他们在肿瘤等疾病中的作用。王艇实验室研究重点是正常发育，疾病发展，和进化过程中细胞命运的决定。实验室同时开发调控网络研究中的应用算法，和大型基因学和表观基因学数据整合方法，包括被广泛应用的华大表观组学浏览器。他目前领导多项NIH的大课题，包括主导NIH的三个大型数据中心：人类泛基因组工程数据中心（Human Pangenome Reference Consortium），环境表观基因组数据中心（NIEHS Environmental Epigenomics Data Center），和遗传变异功能计划中心（Impact of Genetic Variation on Function Consortium）。
报告题目：The WashU Epigenome Browser – Visualizing Genomes in 3D
国家自然科学基金“优青”项目获得者，国家重点研发计划青年科学家项目首席。运用基因组学、分子生物学、基因编辑和人工智能等多学科手段，解析棉花纤维发育和品质形成的遗传基础，揭示染色质高级结构对性状形成的调控机制。在Nature Genetics (3)、Nature Plants、Genome Biology (2)、Nucleic Acids Research、Molecular Biology and Evolution等国际知名期刊发表研究论文20余篇。
His group uses the cotton genus as a research model to investigate the regulatory mechanism of single-cell differentiation and development in plants, committed to improving fiber quality in cotton. He also has interests in the intertwining relationship between genome size evolution and reorganization of higher-order chromatin structure in plants. He extends his research to address some fundamental scientific questions in polyploid plants, such as the underlying mechanism of polyploid advantage in changing environments.
报告题目：Pan-3D genome in the cotton genus and evolution of transcriptional regulation
报告摘要：Plant genomes are not randomly positioned in the nucleus but are packed into higher-order chromatin structures that have important functional implications. In cotton, we assemble reference-grade genome sequences and are interested to know how the linear DNA sequences are packed, the evolutionary process of 3D genome structures between closely related species and their regulatory roles in gene transcription. With the application of Hi-C and related techniques, we obtained the following observations: 1) Genomic structural variations (SVs) preferred occurring in topologically associating domain (TAD) interior instead of TAD boundary and had a large effect on disrupting TAD organization following polyploidization, which led to expression difference of orthologous genes. 2) Active transposon amplification was associated with the increase of the proportion of A compartment in gene regions and had a role in the formation of lineage-specific T AD boundaries. 3) In fiber development, subgenome-relayed switching of the chromatin compartment from active to inactive is coupled with the silencing of developmentally repressed genes, and dissolution of intricate TAD-like structure cliques showing long-range interactions represents a prominent characteristic at the later developmental stage. Dynamic chromatin loops are found to mediate the rewiring of gene regulatory networks that exhibit a significant difference between the At and Dt subgenomes, implicating expression bias of homoeologous genes. These results highlight the necessity of 3D genome study for understanding the reorganization of higher-order chromatin structure and addressing transcriptional regulation evolution underlying agronomic traits in crops.
单位：复旦大学生殖与发育研究院（Reproductive and developmental research institute of Fudan university）
报告题目：Genome-wide prediction of structural variations and enhancer-hijacking events from chromatin interaction data in cancer genomes
报告摘要：Recent efforts have shown that structural variations (SVs) can disrupt three-dimensional genome organization and induce enhancer hijacking, yet no computational tools exist to identify such events from chromatin interaction data. To fill this gap, we develop EagleC, a computational framework that combines deep-learning and ensemble-learning strategies to predict a full range of SVs from chromatin interaction data; and NeoLoopFinder, a framework to identify novel chromatin interactions induced by SVs. Our approaches can automatically resolve complex SVs, reconstruct local Hi-C maps surrounding the breakpoints, normalize copy number variation and allele effects, and predict chromatin loops induced by SVs. We applied our approaches in Hi-C data from 50 cancer cell lines and primary tumors and identified tens of recurrent genes associated with enhancer hijacking. To experimentally validate our approaches, we deleted the hijacked enhancers in prostate adenocarcinoma cells using CRISPR-Cas9, which significantly reduced expression of the target oncogene. In summary, our approaches enable identification of critical oncogenic regulatory elements that can potentially reveal therapeutic targets.
Qin Xiao†1, Xingyu Huang†1, 2, Yan Zhang1, 2, Wei Xu3, Yongqing Yang1, Qing Zhang1, Zhe Hu4, Feng Xing5, Qianwen Sun3, Guoliang Li1, 2 & Xingwang Li*1
Presenting author: email@example.com
报告摘要：Chromatin-associated RNAs play key roles in various biological processes. However, their repository and conjugation genomic loci as well as potential functions remain largely unclear. Here, we develop an effective method for mapping chromatin-associated RNA-DNA interactions, followed by paired-end-tag sequencing (ChRD-PET) in rice. We present a comprehensive interaction map between RNAs and H3K4me3-marked regions based on the H3K4me3 ChRD-PET data, showing three types of RNA-DNA interactions including local, proximal and distal interactions. We further characterize the origin and composition of RNA strand in R-loop RNA-DNA hybrids and identify extensive cis and trans RNAs including trans ncRNAs are prevalently involved in R-loop. Integrative analysis of rice epigenome and 3D genome data suggest coding and non-coding RNAs (ncRNAs) extensively engage in the formation of chromatin loops and chromatin interacting domains. Altogether, ChRD-PET is an efficient method to study the features of RNA-chromatin interactions, and the resulting datasets constitute a valuable resource for studying RNAs and their biological functions.
1 National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China.
2 Hubei Key Laboratory of Agricultural Bioinformatics and Hubei Engineering Technology Research Center of Agricultural Big Data, 3D Genomics Research Center, Huazhong Agricultural University, Wuhan, China
3 Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, Tsinghua University, Beijing, China.
4 State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.
5 College of Life Science, Xinyang Normal University, Xinyang, China.
岳峰 美国西北大学终身讲席教授 生化与遗传学系、病理学系教授
Robert H. Lurie综合癌症研究中心基因组学中心主任，西北大学智能医学所分子研究中心主任。
于2008年在南卡罗来纳大学获得计算机科学与工程博士学位，随后在加州大学圣地亚哥分校任兵实验室从事博士后研究。先后领导或参与了多项美国国立卫生研究所资助的项目，包括ENCODE、Roadmap/Epigeomics、4D Nucleome以及IGVF等。实验室主要致力于人类疾病表观基因组和三维基因组的研究。近年来揭示了基因组、表观基因组以及三维基因组在多种癌症中的深刻变化及其对异常基因表达的影响. 其课题组在Nature、Nature Methods、Nature Genetics、Genome Biology、Nature Communications、Science Advances等期刊发表论文40余篇，SCI他引13000余次。
报告题目：3D genome alteration in pediatric and adult leukemia
报告摘要：Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases.The extent to which mutations in AML drive alterations in chromatin 3D structure and contribute to myeloid transformation is unclear. Here we use Hi-C and whole-genome sequencing to analyse 25 samples from patients with AML and 7 samples from healthy donors. Recurrent and subtype-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing, ATAC with sequencing and CUT&Tag for CTCF, H3K27ac and H3K27me3 in the same AML samples also revealed extensive and recurrent AML-specific promoter–enhancer and promoter–silencer loops. We validated the role of repressive loops on their target genes by CRISPR deletion and interference. Structural variation-induced enhancer-hijacking and silencer-hijacking events were further identified in AML samples. Hijacked enhancers play a part in AML cell growth, as demonstrated by CRISPR screening, whereas hijacked silencers have a downregulating role, as evidenced by CRISPR-interference-mediated de-repression. Finally, whole-genome bisulfite sequencing of 20 AML and normal samples revealed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Treatment of AML cells with a DNA hypomethylating agent and triple knockdown of DNMT1, DNMT3A and DNMT3B enabled the manipulation of DNA methylation to revert 3D genome organization and gene expression. Overall, this study provides a resource for leukaemia studies and highlights the role of repressive loops and hijacked cis elements in human diseases.
郑梅珍 Meizhen Zheng
SUSTech Assistant Professor
简介：南方科技大学生命科学学院，助理教授，课题组PI，博士生导师。深圳市国家级领军人才。2007年在中山大学附属肿瘤防治中心取得肿瘤学博士学位，随后主要在新加坡基因组中心(GIS)、美国杰克逊实验室基因组医学中心(The Jackson Laboratory For Genomic Medicine)进行博士后、副研究员等工作。2019年底加入南方科技大学。主要研究方向为单细胞、单分子水平的3D基因组交互作用技术开发与应用。
Introduction: Dr. Zheng currently is an assistant professor in the School of Life Sciences at Southern University of Science and Technology (SUSTech). She received her Ph.D from Sun Yat-sen University. She continued her postdoctoral training at Genome Institute of Singapore (GIS), then moved to The Jackson Laboratory for Genomic Medicine (JGM) start her career track as Associated Research Scientist in 2017. Dr. Zheng joined SUSTech in 2019. The main focus of her ongoing research is the development and application of 3D genome mapping technologies at the single-cell and single-molecule levels.
报告题目：Development of Chromatin Interaction Capture Methods
报告摘要：The emerging ligation-free three-dimensional (3D) genome mapping technologies can identify multiplex chromatin interactions with single-molecule precision. These technologies offer new insight into high-dimensional chromatin organization and gene regulation, but also introduce new challenges in data visualization and analysis. We developed a toolkit for Multi-way Chromatin Interaction (MCI) analysis, including a visualization tool and platforms for identifying micro-domains with clustered single-molecule chromatin complexes. Furthermore, we describe an approach for investigating RNA-mediated chromatin DNA-DNA interactions (rDD). Using Epstein-Barr virus (EBV) immortalized resting B-lymphocytes, we performed rDD assays to identify EBV noncoding RNAs mediated chromatin contacts between the virus and host.
报告题目：A dynamic kissing model for enhancer-promoter communication on the surface of transcriptional condensate
报告摘要：Enhancer-promoter (E-P) communication is key to gene transcription regulation in eukaryotes. The formation of transcriptional condensates, which might be caused by liquid-liquid phase separation, has been considered as an important mechanism for E-P contacts. However, the detailed kinetic mechanism of how the condensates mediate E-P contacts, and how such contacts may regulate gene transcription remain unclear. Here, we proposed a polymer physics-based E-P communication model. By comparing multiple model settings, we found that one scenario matches experimental data most when E-P contacts were constrained to the spherical surface of condensates. Based on this observation, we proposed a model of gene expression regulation with E-P dynamically kissing on the surface of transcriptional condensates. Last, we demonstrated that a seeming contradiction of gene expression bursting observed in the single-molecular tracking data can be well explained by this model. In summary, we proposed a coarse-grained yet effective model of E-P dynamic kissing, which will facilitate a more comprehensive understanding of enhancer-mediated gene regulation.
研究方向为三维基因组、DNA甲基化相关软件开发、数据分析及数据库构建等工作，开发了DNA甲基化分析软件BatMeth2、首个等位特异性DNA甲基化检测软件MethHaplo，构建了首个等位特异性DNA甲基化数据库ASMdb以及首个蛋白介导的多物种染色质环数据库ChromLoops，相关成果以第一作者（含并列第一作者）发表在Nucleic Acids Research、Genome Biology、BMC Bioinformatics、Plant Physiology等期刊共6篇。
报告题目：ChromLoops: a comprehensive database for speciﬁc protein-mediated chromatin loops in diverse organisms
报告摘要：Chromatin loops (or chromatin interactions) are important elements of chromatin structures. Disruption of chromatin loops is associated with many diseases, such as cancer and polydactyly. A few methods, including ChIA-PET, HiChIP and PLAC-Seq, have been proposed to detect high-resolution, specific protein-mediated chromatin loops. With rapid progress in 3D genomic research, ChIA-PET, HiChIP and PLAC-Seq datasets continue to accumulate, and effective collection and processing for these datasets are urgently needed. Here, we developed a comprehensive, multispecies and specific protein-mediated chromatin loop database (ChromLoops, https://3dgenomics.hzau.edu.cn/chromloops), which integrated 1030 ChIA-PET, HiChIP and PLAC-Seq datasets from 13 species, and documented 1 491 416 813 high-quality chromatin loops. We annotated genes and regions overlapping with chromatin loop anchors with rich functional annotations, such as regulatory elements (enhancers, super-enhancers and silencers), variations (common SNPs, somatic SNPs and eQTLs), and transcription factor binding sites. Moreover, we identified genes with high-frequency chromatin interactions in the collected species. In particular, we identified genes with high-frequency interactions in cancer samples. We hope that ChromLoops will provide a new platform for studying chromatin interaction regulation in relation to biological processes and disease.
2014年毕业于中科院国家纳米科学中心梁兴杰组，物理化学专业博士，曾先后在清华大学张奇伟组，戴琼海组从事博士后研究工作。主要研究领域为利用多肽，核酸等生物大分子进行自组装，实现药物递送以及荧光探针标记成像。已在Advanced Materials，ACS Nano，ACS Applied Materials & Interfaces，IEEE Transactions on Medical Imaging等国际一流期刊发表SCI收录期刊论文35篇，国内专利授权3项，PCT一项。
张玉波 研究员 中国农科院深圳农业基因所
报告题目：Precise genome annotation: a new voyage for 3D genomics
报告摘要：Artificial intelligence (AI) has been emerging as a powerful tool for analyzing genomic data, which will lead to more sophisticated innovations in the future. Precise genome annotation, especially regulatory elements (REs), is the key to the development and the 3D genomics. With current knowledge, the defined REs contain sequence redundancy, which makes the genome context unintelligible. To figure this out, we developed a method termed MAE-seq (Massive Active Enhancers by Sequencing) to experimentally identify functional REs at a 25-bp scale. In this study, more than 1.48 million active enhancers were identified in mouse embryonic stem cells. Comparative analysis indicates most histone modification datasets could be annotated by MAE-Seq loci. Additionally, 35.14% (522,432) are identified as de novo ones without any epigenetic modification. Validation results show that these 25-bp sequences could act as a functional unit, which shows identical or similar expression patterns as the previously defined larger elements. Discovered novel elements that can also up-regulate gene activity. By integrating with Hi-C data, over 55.69% of them may have distal associations with different targeted genes. Our study provides an experimental approach to refine the functional REs at 25-bp resolution, and it will unscramble the underlying genome context for proper cell fate determination, which relies on precise spatial and temporal genome-wide cooperativities among regulatory elements (REs) and their targeted genes.