Biology subjects

Zhao, Y.

Publications and source records attributed to Zhao, Y..

At least 775 records · Page 43Linked to original sources

bioRxiv2022

Near-atomic Structure of the Cytoplasmic Ring of the Xenopus laevis Nuclear Pore Complex

The nuclear pore complex (NPC) mediates nucleocytoplasmic shuttling. Here we present single-particle cryo-EM structure of the cytoplasmic ring (CR) from the Xenopus laevis NPC at 4.1-4.7 [A] resolutions. The structure of an N-terminal domain of Nup358 was resolved at 3.0 [A], facilitating identification of five Nup358 molecules in each CR subunit. Aside from unveiling the assembly details of the two Y-shaped multicomponent complexes (Y complexes) in each CR subunit, the improved resolutions reveal the C-terminal fragment of Nup160 to be an organizing center at the vertex of each Y complex. Our structures show that the scaffold of a CR subunit comprises five Nup358, two Nup205 and two Nup93 molecules in addition to the previously characterized Y complexes. One-Sentence SummaryImproved resolutions of the cytoplasmic ring (CR) of the Xenopus laevis nuclear pore complex reveal that five Nup358 molecules, together with two copies of interweaved Nup205, Nup93 and Y complexes, constitute the scaffold of each CR subunit.

biophysics↗

bioRxiv2022

dbDEMC 3.0: Functional Exploration of Differentially Expressed miRNAs in Cancers of Human and Model Organisms

microRNAs (miRNAs) are important regulators in gene expression. The deregulation of miRNA expression is widely reported in the transformation from physiological to pathological state of cells. A large amount of differentially expressed miRNAs (DEMs) have been identified in various human cancers by using high-throughput technologies, such as microarray and miRNA-seq. Through mining of published researches with high-throughput experiment information, the database of differentially expressed miRNAs in human cancers (dbDEMC) was constructed with the aim of providing a systematic resource for the storage and query of the DEMs. Here we report an update of the dbDEMC to version 3.0, containing two-fold more data entries than the previous version, now including also data from mouse and rat. The dbDEMC 3.0 contains 3,268 unique DEMs in 40 different cancer types. The current datasets for differential expression analysis have expanded to 9 generalized categories. Moreover, the current release integrates functional annotations of DEMs obtained from experimentally validated targets. The annotations can greatly benefit integrative analysis of DEMs. In summary, dbDEMC 3.0 provides a valuable resource for characterizing molecular functions and regulatory mechanisms of DEMs in human cancers. The dbDEMC 3.0 is freely accessible at https://www.biosino.org/dbDEMC.

bioinformatics↗

bioRxiv2022

Study on gene knockout mice and human mutant individual reveals absence of CEP78 causes photoreceptor and sperm flagella impairments

BackgroundCone-rod dystrophy (CRD) is a genetically inherited retinal disease characterized by photoreceptor degeneration. In some rare cases, CRD and hearing loss can be associated with male fertility, while the underlying mechanism is not well known. MethodsUsing CRISPR/Cas9 system, we generated Cep78-/- mice. And electroretinogram (ERG), immunofluorescence staining and transmission electron microscopy (TEM) were used to analyze visual function and photoreceptor ciliary structure changes in Cep78-/- mouse. HE/PAS staining, scanning-electron microscopy (SEM) were conducted to Cep78-/- mice and human CRD patient with CEP78 protein loss to illustrate male infertility and multiple morphological abnormalities of the sperm flagella (MMAF) caused by CEP78 deficiency. TEM and immunofluorescence staining were performed to characterize morphological and molecular changes of sperm flagella microtubule arrangement, centriole development and spermatid head shaping in Cep78-/- mice. Mass-spectrometry analyses were conducted to identify protein abnormalities after Cep78 deletion and Cep78 interacting proteins in spermiogenesis. Co-immunoprecipitation was used to show the Cep78-Ift20-Ttc21a trimer. The role of Cep78-Ift20-Ttc21a trimer in cilliogenesis and centriole elongation was assessed by cilia induction assay. ResultsCep78 knockout mice exhibited impaired function and morphology of photoreceptors, typified by reduced electroretinogram amplitudes, disrupted translocation of cone arrestin, attenuated and disorganized photoreceptor outer segments (OS) disks and widen OS bases, as well as interrupted cilia elongations and structures. Cep78 deletion also caused male infertility and MMAF, with disordered "9 + 2" structure and triplet microtubules in sperm flagella. CEP78 forms a trimer with intraflagellar transport (IFT) proteins IFT20 and TTC21A essential for sperm flagella formation, is essential for their interaction and stability, and recruits IFT20 to centrosome. Insufficiency of any component in the trimer causes centriole elongation and cilia shortening. Additionally, absence of CEP78 protein in human leaded to similar phenotypes in vision and MMAF as Cep78-/- mice. ConclusionsWe found CEP78 as the causative gene of CRD with MMAF in human and mouse. Cep78 forms a trimer with Ift20 and Ttc21a, and regulate the interaction, stability and localization of the trimer proteins, which regulate cilliogenesis, centriole length, and sperm flagella formation. FundingThis work was supported by the National Key R&D Program (2021YFC2700200 to X.G); National Natural Science Foundation of China (82020108006, 81730025 to C.Z, 81971439, 81771641 to X.G, 82070974 to X.C, 82060183 to X.S); Shanghai Outstanding Academic Leaders (2017BR013 to C.Z); and Six Talent Peaks Project in Jiangsu Province (YY-019 to X.G). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

developmental biology↗

bioRxiv2022

Expansion and Adaptive Evolution of the mTERF Gene Family in Plants

Mitochondrial transcription termination factor (mTERF) genes are encoded in the nucleus and bind to nucleic acids to regulate the replication, transcription and translation of mitochondrial genomes. Plants possess a large family of mTERF genes that play important roles in regulating organellar gene expression and stress response. However, their origin and expansion in land plants has not been examined. Here, we conducted a comprehensive molecular evolution analysis of 611 mTERF genes identified in 18 plant species, including algae, moss, fern, gymnosperm and flowering plants. Higher plants have more mTERF genes compared to lower plants, forming a huge higher plant-specific clade (M-class mTERF genes). M-class mTERF genes occur in clusters, suggesting that tandem duplication contributed to their expansion. Compared to other mTERF genes, M-class mTERF genes have undergone rapid evolution, and several significant positively selected sites were located in nucleic acid-binding sites. The strong correlation between the number of M-class mTERF genes and corresponding mitochondrial genome variation suggests that the rapid evolution of M-class mTERF genes might account for the changes in the complex machinery for expression regulation of plant mitochondrial genomes, providing molecular evidence for the host-parasite interaction hypothesis between the nucleus and mitochondria.

plant biology↗

bioRxiv2022

Collateral cleavage of 28s rRNA by RfxCas13d causes death of mice

The CRISPR-Cas13 system is an RNA-guided RNA-targeting system, and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still controversial whether Cas13 exhibits collateral activity in mammalian cells. Here, we found that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which was not resulted from the loss of target gene function or off-target effects. Mechanistically, we showed that RfxCas13d exhibited collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAK-JNK/p38-immediate early gene (IEG) pathway. These results provide new mechanistic insights into the collateral activity of RfxCas13d and warn that the biosafety of CRISPR-Cas13 system needs further evaluation before applying it to clinical treatments.

bioengineering↗

bioRxiv2022

piggyBac-system-mediated genomic integration of large variant libraries for deep mutational scanning in mammalian cells

Deep mutational scanning (DMS) makes it possible to perform massively parallel quantification of the relationship between genetic variants and phenotypes of interest. However, the difficulties in introducing large variant libraries into mammalian cells greatly hinder DMS under physiological states. Here we developed two novel strategies for DMS library construction in mammalian cells, namely piggyBac-in-vitro ligation and piggyBac-in-vitro ligation-PCR. For the first strategy, we took the in-vitro ligation approach to prepare high-diversity linear dsDNAs, and integrate them into the mammalian genome with a piggyBac transposon system. For the second strategy, we further added a PCR step using the in-vitro ligation dsDNAs as templates, for the construction of high-content genome-integrated libraries via large-scale transfection. Both strategies could successfully establish genome-integrated EGFP-chromophore randomized libraries in HEK293T cells and enrich the green fluorescence-chromophore amino acid sequences. And we further identified a novel transcriptional activator peptide with the piggyBac-in-vitro ligation-PCR strategy. Our novel strategies greatly facilitate the construction of large variant DMS library in mammalian cells, and may have great application potential in the future.

bioengineering↗

bioRxiv2022

Germline-soma Supply Mitochondria for mtDNA Inheritance in Mouse Oogenesis

Maternal transmission paradigm of mtDNA remains controversial in mammalian oogenesis. Germline-soma-to-oocyte communication by numerous transzonal nanotubes (TZTs) reminds whether intercellular mitochondrial transfer is associated with maternal inheritance. Here, we found that mouse oocytes egocentrically receive mitochondria via TZTs, which projected from germline-soma, to achieve 105 copies, instead of de novo synthesis of mtDNA subpopulation in growing oocytes. De novo assembled TZTs amongst germline-soma and oocytes accumulated mtDNA amounts of the oocytes in vitro. However, mitochondrial supplement from germline-soma gradually diminished along with oocyte growth and was terminated by meiosis resumption, in line with a decrease in the proportion of germline-soma with thriving mtDNA replication and FSH capture capability. Thus, germline-soma-to-oocyte mitochondrial transfer is responsible for mammalian mtDNA inheritance as well as oogenesis and aging. One-sentence summariesThe maternal mtDNA transmission accompanied by oogenesis is inseparable from germline-soma mitochondrial transport.

developmental biology↗

bioRxiv2022

A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections

SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1+ individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1+ patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections. HighlightsO_LICOVID-19 and HIV-1+ patients show disease-specific inflammatory immune signatures C_LIO_LICOVID-19 patients show more productive humoral responses than HIV-1+ patients C_LIO_LISARS-CoV-2 elicits more enriched IFN-I signaling relative to HIV-I C_LIO_LIDivergent, impaired metabolic programs distinguish SARS-CoV-2 and HIV-1 infections C_LI

bioinformatics↗

bioRxiv2022

Hypoxia Dynamically Regulates DBC1 Ubiquitination and Stability by SIAH2 and OTUD5 in Breast Cancer Progression

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is dynamically regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted the competitive binding of SIAH2 with OTUD5 to DBC1, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin-proteasome pathway. Siah2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of Siah2/DBC1. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.

cell biology↗

bioRxiv2021

Two distinct binding modes provide the RNA binding protein RbFox with extraordinary sequence specificity

The specificity of RNA-binding proteins for their target sequences varies considerably. Yet, it is not understood how certain proteins achieve markedly higher sequence specificity than most others. Here we show that the RNA Recognition Motif of RbFox accomplishes extraordinary sequence specificity by employing functionally and structurally distinct binding modes. Affinity measurements of RbFox for all binding site variants reveal the existence of two different binding modes. The first exclusively binds the cognate and a closely related RNA variant with high affinity. The second mode accommodates all other RNAs with greatly reduced affinity, thereby imposing large thermodynamic penalties on even near-cognate sequences. NMR studies indicate marked structural differences between the two binding modes, including large conformational rearrangements distant from the RNA binding site. Distinct binding modes by a single RNA binding module explain extraordinary sequence selectivity and reveal an unknown layer of functional diversity, cross talk and regulation for RNA-protein interactions.

biochemistry↗

bioRxiv2021

An early Cambrian polyp reveals an anemone-like ancestor for medusozoan cnidarians

Extant cnidarians are a disparate phylum of non-bilaterians and their diploblastic body plan represents a key step in animal evolution. Anthozoans (anemones, corals) are benthic polyps, while adult medusozoans (jellyfishes) are dominantly pelagic medusae. A sessile polyp is present in both groups and is widely conceived as the ancestral form of their last common ancestor. However, the nature and anatomy of this ancestral polyp, particularly of medusozoans, are controversial, owing to the divergent body plans of both groups in the extant lineages and the rarity of medusozoan soft tissues in the fossil record. Here we redescribe the enigmatic Conicula striata Luo et Hu from the early Cambrian Chengjiang biota, south China, which has previously been interpreted as a polyp, lophophorate or deuterostome. We show that C. striata possessed features of both anthozoans and medusozoans. Its stalked polyp and fully encasing conical, annulated organic skeleton (periderm) are features of medusozoans. However, the gut is partitioned by [~]28 mesenteries, and has a tubular pharynx, resembling anthozoans. Our phylogenetic analysis recovers C. striata as a stem medusozoan, indicating that the enormously diverse medusozoans were derived from an anemone-like ancestor, with the pharynx lost and number of mesenteries reduced prior to the origin of crown group Medusozoa.

paleontology↗

bioRxiv2021

Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein.

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S6) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.

microbiology↗

bioRxiv2021

Super-resolution vibrational imaging using expansion stimulated Raman scattering microscopy

Stimulated Raman scattering (SRS) microscopy is an emerging technology that provides high chemical specificity for endogenous biomolecules and can circumvent common constraints of fluorescence microscopy including limited capabilities to probe small biomolecules and difficulty resolving many colors simultaneously due to spectral overlap. However, the resolution of SRS microscopy remains governed by the diffraction limit. To overcome this, we describe a new technique called Molecule Anchorable Gel-enabled Nanoscale Imaging of Fluorescence and stImulatEd Raman Scattering microscopy (MAGNIFIERS), that integrates SRS microscopy with expansion microscopy (ExM). ExM is a powerful strategy providing significant improvement in imaging resolution by physical magnification of hydrogel-embedded preserved biological specimens. MAGNIFIERS offers chemical-specific nanoscale imaging with sub-50 nm resolution and has scalable multiplexity when combined with multiplex Raman probes and fluorescent labels. We used MAGNIFIERS to visualize nanoscale features in a label-free manner with C-H vibration of proteins, lipids and DNA in a broad range of biological specimens, from mouse brain, liver and kidney to human lung organoid. In addition, we applied MAGNIFIERS to track nanoscale features of protein synthesis in protein aggregates using metabolic labeling of small metabolites. Finally, we used MAGNIFIERS to demonstrate 8-color nanoscale imaging in an expanded mouse brain section. Overall, MAGNIFIERS is a valuable platform for super-resolution label-free chemical imaging, high-resolution metabolic imaging, and highly multiplexed nanoscale imaging, thus bringing SRS to nanoscopy.

bioengineering↗

bioRxiv2021

Multiscale 3D Genome Reorganization during Skeletal Muscle Stem Cell Lineage Progression and Muscle Aging

3D genome rewiring is known to influence spatiotemporal expression of lineage-specific genes and cell fate transition during stem cell differentiation and aging processes. Yet it is unknown how 3D architecture remodels and orchestrates transcriptional changes during skeletal muscle stem cell (also called satellite cell, SC) activation, proliferation and differentiation course. Here, using in situ Hi-C we comprehensively map the 3D genome topology reorganization at multiscale levels during mouse SC lineage progression and integrate with transcriptional and chromatin signatures to elucidate how 3D genome rewiring dictates gene expression program. Specifically, rewiring at compartment level is most pronounced when SC becomes activated. Striking loss in TAD border insulation and chromatin looping also occurs during early activation process. Meanwhile, TADs can also form TAD clusters and super-enhancer containing TAD clusters orchestrate stage-specific gene expression during SC early activation. Furthermore, we elucidate 3D chromatin regulation of key transcription factor, PAX7 and identify cis-regulatory elements that are crucial for local chromatin architecture and Pax7 expression. Lastly, 3D genome remodeling is profiled in SCs isolated from naturally aging mice, unveiling that geriatric SCs display a prominent gain in long-range contacts and loss of TAD border insulation. Genome compartmentalization and chromatin looping are evidently altered in aged SC while geriatric SC display a more prominent loss in strength of TAD borders. Together, our results implicate 3D chromatin extensively reorganizes at multiple architectural levels and underpin the transcriptome remodeling during SC lineage development and SC aging.

cell biology↗

bioRxiv2021

Reduced sera neutralization to Omicron SARS-CoV-2 by bothinactivated and protein subunit vaccines and the convalescents

Omicron variant continues to spread all over the world. There are lots of scientific questions remaining to be answered for such a devastating variant. There are a dozen of vaccines already in clinical use. The very urgent scientific question would be whether or not these vaccines can protect Omicron variant. Here, we tested the sera from both convalescents and vaccine recipients receiving either inactivated or protein subunits vaccines (CoronaVac from Sinovac, or BBIBP-CoV from Sinopharm, or ZF2001 from Zhifei longcom) for the binding antibody titers (ELISA) and neutralization antibodies titers (pseudovirus neutralization assay). We showed that Omicron do have severe immune escape in convalescents, with 15 of 16 were negative in neutralization. By contrast, in vaccinees who received three jabs of inactivated or protein subunit vaccine, the neutralizing activity was much better preserved. Especially in the ZF2001 group with an extended period of the second and third jab (4-6 months) remains 100% positive in Omicron neutralization, with only 3.1-folds reduction in neutralizing antibody (NAb) titer. In this case, we proposed that, the multi-boost strategy with an extended interval between the second and third jab for immune maturation would be beneficial for NAb against devastating variants such as Omicron.

immunology↗

bioRxiv2021

The dual role of N6-methyladenosine on mouse maternal RNAs and 2-cell specific RNAs revealed by ULI-MeRIP sequencing

N6-methyladenosine (m6A) and its regulatory components play critical roles in various developmental processes in mammals(1-5). However, the landscape and function of m6A in the maternal-to-zygotic transition (MZT) remain unclear due to limited materials. Here, by developing an ultralow-input MeRIP-seq method, we revealed the dynamics of the m6A RNA methylome during the MZT process in mice. We found that more than 1/3 maternal decay and 2/3 zygotic mRNAs were modified by m6A. Moreover, m6As are highly enriched in the RNA of transposable elements MTA and MERVL, which are highly expressed in oocytes and 2-cell embryos, respectively. Notably, maternal depletion of Kiaa1429, a component of the m6A methyltransferase complex, leads to a reduced abundance of m6A-marked maternal RNAs, including both genes and MTA, in GV oocytes, indicating m6A-dependent regulation of RNA stability in oocytes. Interestingly, when the writers were depleted, some m6A-marked 2-cell specific RNAs, including Zscan4 and MERVL, appeared normal at the 2-cell stage but failed to be decayed at later stages, suggesting that m6A regulates the clearance of these transcripts. Together, our study uncovered that m6As function in context-specific manners during MZT, which ensures the transcriptome stability of oocytes and regulates the stage specificity of zygotic transcripts after fertilization. One Sentence Summarym6A RNA methylation stabilizes the maternal RNAs in mouse oocytes and degrades the 2-cell specific RNAs in the cleavage-stage embryos.

developmental biology↗

bioRxiv2021

MIG-23 is involved in sperm migration in Ascaris suum

In nematodes, spermiogenesis, which is also called sperm activation, is a process in which nonmotile spermatids are transformed into crawling spermatozoa, which is accompanied by a series of morphological, physiological and biochemical changes. Sperm motility acquisition during this process is essential for successful fertilization. However, the mechanisms of sperm motility regulation in nematodes remain to be clarified. Herein, we found that extracellular adenosine-5-triphosphate (ATP) level mediation by MIG-23, which is a homolog of human ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), was required for major sperm protein (MSP) filament dynamics and sperm motility in the nematode Ascaris suum. MIG-23 was localized on the sperm plasma membrane. During sperm activation, mitochondrial activity was increased dramatically, and a large amount of ATP was produced and stored in refringent granules (RGs). In addition, a portion of the produced ATP was released to the extracellular space through ATP channels, which were composed of innexins and localized on the sperm plasma membrane. Spermatozoa, instead of spermatids, hydrolyzed exogenous ATP and processed ecto-ATPase activity. MIG-23 contributed to the ecto-ATPase activity of spermatozoa. Once MIG-23 activity was interrupted, spermatozoa also decreased their ATP hydrolysis activity. Blocking MIG-23 activity resulted in an increase in the depolymerization rate of MSP filaments in pseudopodia, which eventually affected nematode sperm migration. Overall, our data imply that MIG-23, which contributes to the ecto-ATPase activity of spermatozoa, regulates sperm migration by modulating extracellular ATP levels. HighlightsO_LIATP is released to extracellular space through innexin channels which are identified in worm sperm. C_LIO_LIWorm spematozoa show ecto-ATPase activity. C_LIO_LIMIG-23 contributes to the ecto-ATPase activity of spermatozoa and regulates extracellular ATP level. C_LIO_LIMIG-23 is required for MSP-based filament dynamics and sperm migration. C_LI

cell biology↗

bioRxiv2021

Dynamic interplay between structural variations and 3D chromosome organization in pancreatic cancer

Structural variations (SVs) are the greatest source of variation in the genome and can lead to oncogenesis. However, the identification and interpretation of SVs in human pancreatic cancer remain largely undefined due to technological limitations. Here, we investigate the spectrum of SVs and three-dimensional (3D) chromatin architecture in human pancreatic ductal epithelial cell carcinogenesis by using state-of-the-art long- read single-molecule real-time (SMRT) and high-throughput chromosome conformation capture (Hi-C) sequencing techniques. We find that the 3D genome organization is remodeled and correlated with gene expressional change. The bulk remodeling effect of cross-boundary SVs in the 3D genome partly depends on intercellular genomic heterogeneity. Meanwhile, contact domains tend to minimize these disrupting effects of SVs within local adjacent genomic regions to maintain overall stability of 3D genome organization. Moreover, our data also demonstrates complex genomic rearrangements involving two key driver genes CDKN2A and SMAD4, and elucidates their influence on cancer-related gene expression from both linear view and 3D perspective. Overall, this study provides a valuable resource and highlights the impact, complexity and dynamicity of the interplay between SVs and 3D genome organization, which further expands our understanding of pathogenesis of SVs in human pancreatic cancer.

genetics↗