Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 919 records · Page 51Linked to original sources

bioRxiv2019

Comparison of three different eye-tracking tasks for distinguishing autistic from typically developing children and autistic symptom severity

Altered patterns of visual social attention preference detected using eye-tracking and a variety of different paradigms are increasingly proposed as sensitive biomarkers for autism spectrum disorder. However, few eye tracking studies have compared the relative efficacy of different paradigms to discriminate between autistic compared with typically developing children and their sensitivity to specific symptoms. To target this issue, the current study used three common eye tracking protocols contrasting social versus non-social stimuli in young (2-7 years old) Chinese autistic (n = 35) and typically developing (n = 34) children matched for age and gender. Protocols included dancing people vs. dynamic geometrical images, biological motion (dynamic light point walking human or cat) vs. non-biological motion (scrambled controls) and child playing with toy vs. toy alone. Although all three paradigms differentiated autistic and typically developing children, the dancing people versus dynamic geometry pattern paradigm was the most effective, with autistic children showing marked reductions in visual preference for dancing people and correspondingly increased one for geometric patterns. Furthermore, this altered visual preference in autistic children was correlated with the ADOS social affect score and had the highest discrimination accuracy. Our results therefore indicate that decreased visual preference for dynamic social stimuli may be the most effective visual attention-based paradigm for use as a biomarker for autism in Chinese children. Clinical trial ID: NCT03286621 (clinicaltrials.gov); Clinical trial name: Development of Eye-tracking Based Markers for Autism in Young Children. Lay summaryEye-tracking measures may be useful in aiding diagnosis and treatment of autism, although it is unclear which specific tasks are optimal. Here we compare the ability of three different social eye-gaze tasks to discriminate between autistic and typically developing young Chinese children and their sensitivity to specific autistic symptoms. Our results show that a dynamic task comparing visual preference for social (individuals dancing) versus geometric patterns is the most effective both for diagnosing autism and sensitivity to its social affect symptoms.

clinical trials↗

bioRxiv2019

An Array of 60,000 Antibodies for Proteome-Scale Antibody Generation and Target Discovery

Antibodies are essential for elucidating the roles of genes decoded by genome sequencing. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed the Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 mAbs against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic feature of an antibody. Distinctive combinations of 10,000-20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-target pairs were discovered for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for human membrane proteins and ChIP-seq mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues discovered internalizing tumor antigens for antibody-drug conjugates. By discovering high affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.

systems biology↗

bioRxiv2019

Lifelong genetically lowered sclerostin and risk of cardiovascular disease.

BackgroundInhibition of sclerostin is a novel therapeutic approach to lowering fracture risk. However, phase III randomised controlled trials (RCTs) of romosozumab, a monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events. MethodsWe used two independent genetic variants (rs7209826 and rs188810925) in SOST (encoding sclerostin) associated with bone mineral density (BMD) as proxies for therapeutic inhibition of sclerostin. We estimated the effects on risk of osteoporosis, fracture, coronary heart disease (CHD) and a further 22 cardiometabolic risk factors and diseases, by combining data from up to 478,967 participants of European ancestry from three prospective cohorts and up to 1,030,836 participants from nine GWAS consortia. In addition, we performed meta-analyses of cardiovascular outcome data from phase III RCTs of romosozumab. ResultsMeta-analysis of RCTs identified a higher risk of cardiac ischemic events in patients randomised to romosozumab (25 events among 4,298 individuals; odds ratio [OR] 2{middle dot}98; 95% confidence interval [CI], 1{middle dot}18 to 7{middle dot}55; P=0{middle dot}017). Scaled to the equivalent dose of romosozumab (210mg/month; 0{middle dot}09 g/cm2 higher BMD), the SOST variants associated with lower risk of fracture (OR, 0{middle dot}59; 95% CI, 0{middle dot}54-0{middle dot}66; P= 1{middle dot}4x10-24), and osteoporosis (OR, 0{middle dot}43; 95% CI, 0{middle dot}36-0{middle dot}52; P=2{middle dot}4x10-18). The SOST variants associated with higher risk of myocardial infarction and/or coronary revascularisation (69,649 cases; OR, 1{middle dot}18; 95% CI, 1{middle dot}06-1{middle dot}32; P=0{middle dot}003) and type 2 diabetes (OR 1{middle dot}15; 95% CI, 1{middle dot}05-1{middle dot}27; P=0{middle dot}003), higher systolic blood pressure (1{middle dot}3mmHg; 95% CI 0{middle dot}8-1{middle dot}9; P=5{middle dot}9x10-6) and waist-to-hip-ratio adjusted for BMI (0{middle dot}05 SDs; 95% CI, 0{middle dot}02 to 0{middle dot}08; P=8{middle dot}5x10-4). ConclusionsGenetically and therapeutically lowered sclerostin leads to higher risk of cardiovascular events. Rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors is warranted.

genetics↗

bioRxiv2019

Conditional Guide RNAs: Programmable Conditional Regulation of CRISPR/Cas Function in Bacteria via Dynamic RNA Nanotechnology

A guide RNA (gRNA) directs the function of a CRISPR protein effector to a target gene of choice, providing a versatile programmable platform for engineering diverse modes of synthetic regulation (edit, silence, induce, bind). However, the fact that gRNAs are constitutively active places limitations on the ability to confine gRNA activity to a desired location and time. To achieve programmable control over the scope of gRNA activity, here we apply principles from dynamic RNA nanotechnology to engineer conditional guide RNAs (cgRNAs) whose activity is dependent on the presence or absence of an RNA trigger. These cgRNAs are programmable at two levels, with the trigger-binding sequence controlling the scope of the effector activity and the target-binding sequence determining the subject of the effector activity. We demonstrate molecular mechanisms for both constitutively active cgRNAs that are conditionally inactivated by an RNA trigger (ON[->]OFF logic) and constitutively inactive cgRNAs that are conditionally activated by an RNA trigger (OFF[->]ON logic). For each mechanism, automated sequence design is performed using the reaction pathway designer within NUPACK to design an orthogonal library of three cgRNAs that respond to different RNA triggers. In E. coli expressing cgRNAs, triggers, and silencing dCas9 as the protein effector, we observe programmable conditional gene silencing with a median dynamic range of {approx}6-fold for an ON[->]OFF \"terminator switch\" mechanism, {approx}15-fold for an ON[->]OFF \"splinted switch\" mechanism, and {approx}3.6-fold for an OFF[->]ON \"toehold switch\" mechanism; the median crosstalk within each cgRNA library is <2%, <2%, and {approx}20% for the three mechanisms. By providing programmable control over both the scope and target of protein effector function, cgRNA regulators offer a promising platform for synthetic biology.\n\nO_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

synthetic biology↗

bioRxiv2019

The transferability of lipid-associated loci across African, Asian and European cohorts

The under-representation of non-European samples in genome-wide association studies could ultimately restrict who benefits from medical advances through genomic science. Our aim was therefore to address the fundamental question whether causal variants for blood lipids are shared across populations.\n\nA polygenic score based on established LDL-cholesterol-associated loci from European discovery samples had consistent effects on serum levels in samples from the UK, Uganda and Greek population isolates (correlation coefficient r=0.23 to 0.28 per LDL standard deviation, p<1.9x10-14). Trans-ethnic genetic correlations between European ancestry, Chinese and Japanese cohorts did not differ significantly from 1 for HDL, LDL and triglycerides. In each study, >60% of major lipid loci displayed evidence of replication with one exception. There was evidence for an effect on serum levels in the Ugandan samples for only 10% of major triglyceride loci. The PRS was only weakly associated in this group (r=0.06, SE=0.013). We establish trans-ethnic colocalization as a method to distinguish shared from population-specific trait loci.\n\nOur results provide evidence for high levels of consistency of genetic associations for cholesterol biomarkers across populations. However, we also demonstrate that the degree of shared causal genetic architecture can be population-, trait- and locus-specific. Efforts to implement genetic risk prediction in clinical settings should account for this.

genetics↗

bioRxiv2019

Reproducibility of functional brain alterations in major depressive disorder: evidence from a multisite resting-state functional MRI study with 1,434 individuals

Resting-state functional MRI (R-fMRI) studies have demonstrated widespread alterations in brain function in patients with major depressive disorder (MDD). However, a clear and consistent conclusion regarding a repeatable pattern of MDD-relevant alterations is still limited due to the scarcity of large-sample, multisite datasets. Here, we address this issue by including a large R-fMRI dataset with 1,434 participants (709 patients with MDD and 725 healthy controls) from five centers in China. Individual functional activity maps that represent very local to long-range connections are computed using the amplitude of low-frequency fluctuations, regional homogeneity and distance-related functional connectivity strength. The reproducibility analyses involve different statistical strategies, global signal regression, across-center consistency, clinical variables, and sample size. We observed significant hypoactivity in the orbitofrontal, sensorimotor, and visual cortices and hyperactivity in the frontoparietal cortices in MDD patients compared to the controls. These alterations are not affected by different statistical analysis strategies, global signal regression and medication status and are generally reproducible across centers. However, these between-group differences are partially influenced by the episode status and the age of disease onset in patients, and the brain-clinical variable relationship exhibits poor cross-center reproducibility. Bootstrap analyses reveal that at least 400 subjects in each group are required to replicate significant alterations (an extent threshold of P<.05 and a height threshold of P<.001) at 50% reproducibility. Together, these results highlight reproducible patterns of functional alterations in MDD and relevant influencing factors, which provides crucial guidance for future neuroimaging studies of this disorder.

neuroscience↗

bioRxiv2019

Oxytocin reduces top-down control of attention by increasing bottom-up attention allocation to social but not non-social stimuli

The neuropeptide oxytocin (OXT) may facilitate attention to social stimuli by influencing early stage bottom-up processing although findings in relation to different emotional expressions are inconsistent and its influence on top-down cognitive processing mechanisms unclear. In the current double-blind, placebo (PLC) controlled, between subject design study we therefore recruited 71 male subjects to investigate the effects of intranasal OXT (24IU) on both bottom-up attention allocation and top-down attention inhibition using a visual antisaccade paradigm with concurrent eye movement acquisition. Our results show that OXT increased antisaccade errors for social stimuli (all types of emotional faces), but not shapes. This effect of OXT was modulated by trait behavioral inhibition and there was also evidence for reduced state anxiety after OXT treatment. Antisaccades are under volitional control and therefore this indicates that OXT treatment produced reduced top-down inhibition. However, the overall findings are consistent with OXT acting to reduce top-down control of attention as a result of increasing bottom-up early attentional processing of social, but not non-social, stimuli in situations where the two systems are in potential conflict. This effect of OXT is also modulated by individual levels of trait behavioral inhibition possibly as a result of an anxiolytic action.

neuroscience↗

bioRxiv2019

Multiplexed, sequential secretion analysis of the same single cells reveals distinct effector response dynamics dependent on the initial basal state

The effector response of immune cells dictated by an array of secreted proteins is a highly dynamic process, requiring sequential measurement of all relevant proteins from single cells. Herein we show a microchip-based, 10-plexed, sequential secretion assay on the same single cells and at the scale of ~5000 single cells measured simultaneously over 4 time points. It was applied to investigating the time course of single human macrophage response to Toll-like receptor 4 (TLR4) ligand lipopolysaccharide and revealed four distinct activation modes for different proteins in single cells. In particular, we observed that secreted factors regulated by transcription factor NFO_SCPLOWKC_SCPLOWB (e.g., TNF and CCL2) predominantly show on-off mode over off-on mode. The dynamics of all proteins combined classified the cells into two major activation states, which were found to be dependent on the basal state of each cell. Single-cell RNA-Seq was performed on the same samples at the matched time points and further demonstrated at the transcriptional level the existence of two major activation states, which are enriched for translation vs inflammatory programs, respectively. These results showed a cell-intrinsic heterogeneous response in phenotypically homogeneous cell population. This work demonstrated the longitudinal tracking of protein secretion signature in thousands of single cells at multiple time points, providing dynamic information to better understand how individual immune cells react to pathogenic challenges over time and how they together constitute a population response.

bioengineering↗

bioRxiv2018

Co-allocation Action of Azospirillum brasilense Inoculation and Seed Priming for Improving Germination and Seedling Growth in Aged Grass Seeds

Germination of seeds during the transportation or after prolonged storage naturally and inevitably decreases because of ageing, but germination potential can be partially restored with seed priming treatments. A novel attempt was made to investigate the effects of combined treatments and to optimize the conditions for naturally aged seeds of tall fescue (Festuca arundinacea Schreb.), orchardgrass (Dactylis glomerata L.) and Russian wild rye (Psathyrostachys juncea (Fisch.) Nevski) using an orthogonal activity level experimental design [factor A: Azospirillum brasilense concentration, factor B: three seed priming treatments (H2O, MgSO4 and H2O2) and factor C: different priming times]. Multivariate regression model analysis was applied to determine the interactive effects of pairwise factors (A and C) and to optimize experimental conditions. The results showed that the mixed treatments positively affected seed germination and seedling growth. The three seed priming treatments were the dominant factors for germination promotion, whereas the bacterial concentration had the largest effect on seedling growth, especially root elongation. The combined results of all determined attributes showed that A. brasilense bio-priming with H2O2 priming constituted the optimal combination. The optimal bacterial concentration of A. brasilense and the time of seed priming were 52.3 x 106 colony forming units (CFU) mL-1 and 17.0 h, respectively. We also discussed the physiological mechanisms that could repair aged seeds: the malondialdehyde content and antioxidant enzyme (superoxide dismutase, peroxidase, catalase and ascorbate peroxidase) activities were affected.

plant biology↗

bioRxiv2018

A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells

The most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. Here we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pHe) and CA IX expression. Yet, isoform selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX cooperates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple negative breast cancer (TNBC), appears to coordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H+ shuttle system in CA IX to facilitate proton efflux through MCT4.

cancer biology↗

bioRxiv2018

QTL mapping of leaf angle on eight nodes in maize enable the optimize canopy by differential operating of leaf angle at different levels of plant

Leaf angle (LA) is one of the most important canopy architecture related traits of maize (Zea mays L.). Currently, there is an urgent need to elucidate the genetic mechanism of LA at canopy-wide levels for optimizing dense-planting canopy architecture. In present study, one RIL population derived from two parent lines which show distinct plant architecture was used to perform QTL mapping for LA at eight leaves below the tassel under three environments. Dozens of QTL for LA at eight leaves were identified, which were mapped on all maize chromosomes except for the tenth chromosome. Among them, there were nine common QTL as they were identified for LA more than 1 leaves or in two or three environments. And individual QTL could explain 1.29% - 20.14% of the phenotypic variation and affect LA of 1-8 leaves, including qLA5.1 affected LA of all eight leaves, qLA3.1 affected LA of the upper leaves (1stLA to 4thLA), and qLA9.1 could affect LA of the lower leaves (5thLA to 8thLA). Furthermore, the results indicated that the genetic architecture of LA at eight leaves was different. Specifically, 8thLA was mainly affected by major and minor QTL; 1stLA, 4thLA and 5thLA were affected by epistatic interactions beside major and minor QTL; while the other four LAs were simultaneously affected by major QTL, minor QTL, epistatic interactions and environments. These results provide a comprehensive understanding of genetic basis of LA at canopy-wide levels, which will be beneficial to design ideal plant architecture under dense planting in maize. Author contribution statementJ. L. and D. T. designed and supervised the study, D. T., Z.C., J.N., Q.J., P.L., L.W., J.Z., C.L. performed the phenotypic data collection. D. T. analyzed the data and drafted the manuscript, D. T. and Z.C. revised and finalized the manuscript. All the authors read and approved the manuscript. Key messageDozens of QTL for leaf angle of eight consecutive leaves were identified in the RIL population across three environments, providing the information that optimization of canopy architecture at various canopy levels.

plant biology↗

bioRxiv2018

Migration of gastric cancer is suppressed by rabies virus glycoprotein via regulating α7-nicotinic acetylcholine receptors/ERK-EMT

Nicotinic acetylcholine receptors (nAChRs) have been reported to be overexpressed in malignancies in humans and is associated with tumorigenesis and cell migration. In previous studies of gastric cancer, alpha7 nicotinic acetylcholine receptor (7-nAChR) overexpression can induce epithelial-mesenchymal transition (EMT) and promote migration of gastric cancer cells. Recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing the rabies virus glycoprotein (rL-RVG) may promote apoptosis of gastric cancer cells and reduces migration of lung cancer metastasis. However, whether rL-RVG inhibits migration of gastric cancer cells and what the underlying functional mechanism is remains unknown. In this study, our findings demonstrate that rL-RVG suppressed migration and reduced EMT of gastric cancer cells via 7-nAChR in vitro. Furthermore rL-RVG decreased the phosphorylation levels of the MEK/ERK signaling pathway such as down-regulating the expression of P-MEK and P-ERK. Additionally, rL-RVG also reduced the expression level of mesenchymal markers N-cadherin and Vimentin and enhanced the expression of the epithelial marker E-cadherin. Lastly, rL-RVG together with nicotinic acetylcholine receptors (nAChRs) inhibited gastric cancer epithelial to mesenchymal transition (EMT) which suppressed gastric cancer cell migration. We also found that rL-RVG suppresses the growth of gastric cancer subcutaneous tumor cells in vivo. Thus, rL-RVG inhibits 7-nAChR-MEK/ERK-EMT to suppress migration of gastric cancer cells.

cancer biology↗

bioRxiv2018

Integrated analysis of sex-biased mRNA and miRNA expression profiles in the gonad of the discus fish (Symphysodon aequifasciatus)

The discus fish (Symphysodon aequifasciatus) is an ornamental fish that is well-known around the world. Phenotype investigation indicated that there are no significant differences in appearance between males and females of the discus fish. To better understand the sexual development mechanisms and obtain a high efficiency sex identification method in the artificial reproduction process of the discus fish, we constructed six cDNA libraries from three adult testes and three adult ovaries, and perform RNA-sequencing for identifying sex-biased candidate genes, microRNA (miRNA), and metabolic pathway using the Illumina Hiseq 4000. A total of 50,082 non-redundant genes (unigenes) were identified, of which 18,570 unigenes were significantly overexpressed in testes, and 11,182 unigenes were significantly overexpressed in ovaries, and 8 differentially expressed unigenes were validated by quantitative Real-Time PCR (qPCR). A total of 551 miRNAs were identified, of which 47 miRNAs were differentially expressed between testes and ovaries, and 7 differentially expressed miRNAs and one non-differential miRNA were validated by qPCR. Twenty-four of these differentially expressed miRNAs and their 15 predicted target genes constituted 41 important miRNA-mRNA interaction pairs, which may be important candidates for sex-related miRNAs and sex-related genes in the discus fish. Some of vital sex-related metabolic pathways were also identified that may play key roles in regulating gonad development of the discus fish. These results can provide important insights to better understand molecular mechanisms for sexual dimorphism in gonads development.

genetics↗

bioRxiv2018

Activation and in vivo evolution of the MAIT cell transcriptome in mice and humans reveals diverse functionality

Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells conserved across mammalian species, including mice and humans. By sequencing RNA from sorted MR1-5-OP-RU tetramer+ cells derived from either human blood or murine lungs, we define the basic transcriptome of an activated MAIT cell in both species and demonstrate how this profile changes during resolution and reinfection phases of infection. We observe strong similarities between MAIT cells in humans and mice. Compared with previously published T cell transcriptomes, MAIT cells displayed most similarity to iNKT cells when activated, but to {gamma}{delta} T cells, after resolution of infection. In both species activation leads to strong expression of pro-inflammatory cytokines and chemokines, and also a strong tissue repair signature, recently described in murine commensal-specific H2-M3-restricted T cells. These data define the requirements for, and consequences of, MAIT cell activation, revealing a tissue repair phenotype expressed upon MAIT cell activation in both species.

immunology↗

bioRxiv2018

DNA segment of African Swine Fever Virus first detected in hard ticks from sheep and bovine

In this study, we aimed to detect viruses in hard ticks using the small RNA sequencing based method. A 235-bp DNA segment was detected in Dermacentor nuttalli (hard ticks) and D. silvarum (hard ticks) from sheep and bovine, respectively. The detected 235-bp segment had an identity of 99% to a 235-bp DNA segment of African Swine Fever Virus (ASFV) and contained three single nucleotide mutations (C38T, C76T and A108C). C38T, resulting in an single amino acid mutation G66D, suggests the existence of a new ASFV strain, which is different from all reported ASFV strains in NCBI GenBank database. These results also suggest that ASFV could have a wide range of hosts or vectors, beyond the well known Suidae family and soft ticks. Our findings pave the way toward further studies of ASFV transmission and development of prevention and control measures.

zoology↗

bioRxiv2018

Astroglial dysfunctions drive aberrant synaptogenesis in developing brain with lengthy general anesthesia

Lengthy use of general anesthetics (GAs) causes cognitive deficits in developing brain, which has raised significant clinical concerns such that FDA is warning on the use of GAs in children younger than 3 years. However, the molecular and cellular mechanisms for GAs-induced neurotoxicity remain largely unknown. Here we report that sevoflurane, a commonly used GA in pediatrics, causes compromised astrocyte morphogenesis, spatiotemporally correlated to the synaptic overgrowth with reduced synaptic function in developing cortex in a regional-, exposure-length- and age-specific manner. Sevoflurane disrupts astrocyte Ca2+ homeostasis both acutely and chronically, which leads to the down regulation of Ezrin, an actin-binding membrane protein, which we found is critically involved in astrocyte morphogenesis in vivo. Importantly, in normal developing brain, the genetic intervention of astrocyte morphogenesis is sufficient to produce the aberrant synaptic structure and function virtually identical to the ones induced by lengthy sevoflurane exposure. Our data uncover that astrocytes are unexpectedly central targets for GAs to exert toxic effects, and that astrocyte morphological integrity is crucial for synaptogenesis in the developing brain.

neuroscience↗

bioRxiv2018

Genome-wide co-localization of RNA-DNA interactions and fusion RNA pairs

Fusion transcripts are used as biomarkers in companion diagnoses. Although more than 15,000 fusion RNAs have been identified from diverse cancer types, few common feature has been reported. Here, we compared 16,410 fusion transcripts detected in cancer (from a published cohort of 9,966 tumor samples of 33 cancer types) with genome-wide RNA-DNA interactions mapped in two normal, non-cancerous cell types (using iMARGI, an enhanced version of the MARGI [Mapping RNA-Genome Interactions assay]). Among the top 10 most significant RNA-DNA interactions in normal cells, 5 co-localized with the gene pairs that formed fusion RNAs in cancer. Furthermore, throughout the genome, the frequency of a gene pair to exhibit RNA-DNA interactions is positively correlated with the probability of this gene pair to present documented fusion transcripts in cancer. To test whether RNA-DNA interactions in normal cells are predictive of fusion RNAs, we analyzed in a validation cohort of 96 lung cancer samples using RNA-seq. We found 34 out of 42 fusion transcripts in the validation cohort exhibited RNA-DNA interactions in normal cells. Finally, combining RNA-seq, single-molecule RNA FISH, and DNA FISH, we detected a cancer sample with Eml4-Alk fusion RNA without forming the Eml4-Alk fusion gene. Collectively, these data suggest a novel RNA-poise model, where spatial proximity of RNA and DNA could poise for creation of fusion transcripts.

systems biology↗

bioRxiv2018

Accurate loop calling for 3D genomic data with cLoops

Sequencing-based 3D genome mapping technologies can identify loops formed by interactions between regulatory elements hundreds of kilobases apart. Existing loop-calling tools are mostly restricted to a single data type, with accuracy dependent on a pre-defined resolution contact matrix or called peaks, and can have prohibitive hardware costs. Here we introduce cLoops ( see loops) to address these limitations. cLoops is based on the clustering algorithm cDBSCAN that directly analyzes the paired-end tags (PETs) to find candidate loops and uses a permuted local background to estimate statistical significance. These two data-type-independent processes enable loops to be reliably identified for both sharp and broad peak data, including but not limited to ChIA-PET, Hi-C, HiChIP and Trac-looping data. Loops identified by cLoops showed much less distance-dependent bias and higher enrichment relative to local regions than existing tools. Altogether, cLoops improves accuracy of detecting of 3D-genomic loops from sequencing data, is versatile, flexible, efficient, and has modest hardware requirements, and is freely available at: https://github.com/YaqiangCao/cLoops.

bioinformatics↗