Biology subjects

Zhou, N.

Publications and source records attributed to Zhou, N..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Metagenome-assembled genomes provide insight into the microbial taxonomy and ecology of the Buhera Soda Pans, Zimbabwe

The use of metagenomics has substantially improved our understanding of the taxonomy, phylogeny and ecology of extreme environment microbiomes. Advances in bioinformatics now permit the reconstruction of almost intact microbial genomes, called metagenome-assembled genomes (MAGs), from metagenomic sequence data, allowing for more precise cell-level taxonomic, phylogenetic and functional profiling of uncultured extremophiles. Here, we report on the recovery and characterisation of metagenome-assembled genomes from the Buhera soda pans located in eastern Zimbabwe. This ecosystem has not been studied despite its unique geochemistry and potential as a habitat for unique microorganisms. Metagenomic DNA from the soda pan was sequenced using the DNA Nanoball Sequencing (DNBSEQR) technique. Sequence analysis, done on the Knowledgebase (KBase) platform, involved quality assessment, read assembly, contig binning, and MAG extraction. The MAGs were subjected to taxonomic placement, phylogenetic profiling and functional annotation in order to establish their possible ecological roles in the soda pan ecosystem. A total of 16 bacterial MAGs of medium to high quality were recovered, all distributed among five phyla dominated by Proteobacteria and Firmicutes. Of the ten MAGs that were taxonomically classified up to genus level, five of them belonged to the halophilic/ haloalkaliphilic genera Alkalibacterium, Vibrio, Thioalkalivibrio, Cecembia and Nitrincola. Functional profiling revealed the use of diverse carbohydrate-metabolising pathways among the MAGs, with glycolysis and the pentose phosphate pathways appearing to be key pathways in this ecosystem. Several MAGs harboured both sulphur/ sulphate reduction and respiratory pathways, suggesting a possible mechanism of energy generation through sulphur/ suphate respiration. In conclusion, this study revealed a highly taxonomically and functionally diverse microbial community in the soda pans, dominated by halophilic and haloalkaliphilic bacteria.

microbiology↗

bioRxiv2024

Programmable RNA writing with trans-splicing

RNA editing offers the opportunity to introduce either stable or transient modifications to nucleic acid sequence without permanent off-target effects, but installation of arbitrary edits into the transcriptome is currently infeasible. Here, we describe Programmable RNA Editing & Cleavage for Insertion, Substitution, and Erasure (PRECISE), a versatile RNA editing method for writing RNA of arbitrary length and sequence into existing pre-mRNAs via 5' or 3' trans-splicing. In trans-splicing, an exogenous template is introduced to compete with the endogenous pre-mRNA, allowing for replacement of upstream or downstream exon sequence. Using Cas7-11 cleavage of pre-mRNAs to bias towards editing outcomes, we boost the efficiency of RNA trans-splicing by 10-100 fold, achieving editing rates between 5-50% and 85% on endogenous and reporter transcripts, respectively, while maintaining high-fidelity. We demonstrate PRECISE editing across 11 distinct endogenous transcripts of widely varying expression levels, showcasing more than 50 types of edits, including all 12 possible transversions and transitions, insertions ranging from 1 to 1,863 nucleotides, and deletions. We show high efficiency replacement of exon 4 of MECP2, addressing most mutations that drive the Rett Syndrome; editing of SHANK3 transcripts, a gene involved in Autism; and replacement of exon 1 of HTT, removing the hallmark repeat expansions of Huntington's disease. Whole transcriptome sequencing reveals the high precision of PRECISE editing and lack of off-target trans-splicing activity. Furthermore, we combine payload engineering and ribozymes for protein-free, high-efficiency trans-splicing, with demonstrated efficiency in editing HTT exon 1 via AAV delivery. We show that the high activity of PRECISE editing enables editing in non-dividing neurons and patient-derived Huntingtons disease fibroblasts. PRECISE editing markedly broadens the scope of genetic editing, is straightforward to deliver over existing gene editing tools like prime editing, lacks permanent off-targets, and can enable any type of genetic edit large or small, including edits not otherwise possible with existing RNA base editors, widening the spectrum of addressable diseases.

molecular biology↗

bioRxiv2024

Insights into Human Epileptogenesis with Proteomic Profiling

Epilepsy affects millions globally, and drug-resistant epilepsy remains a challenge. Molecular mechanisms underlying epilepsy remain elusive. Protein profiling through proteomics offers insight into biomarkers and therapeutic targets. Human brain tissue from epilepsy surgeries was analyzed using data-independent acquisition (DIA) proteomics. Samples were categorized into Core (epileptogenic focus), Border (marginal excision tissue), and Nonepileptic control groups. Differential expression proteins (DEPs) were identified and shared proteins were analyzed. 163 DEPs were identified which may has potential roles in the initiation of epileptic electrical firing, 412 DEPs which indicating the difference between epilepsy and Nonepilepsy patients and 10 DEPs consistently altered in Core which indicating potential roles in epileptogenesis. Notably, P35754/GLRX, O75335/PPFIA4, and Q96KP4/CNDP2 were consistently expressed differently in all group pairs. From validation experiments, the expression of Kv3.2 significant reduced in the Core group compare to border group by immunohistochemistry and knockdown of Kv3.2 increased seizure susceptibility and altered neuronal excitability through our cellular and animal experimentation.

neuroscience↗

bioRxiv2023

Experience shapes initial exploration for non-generalizable spatial learning

Experience can change how individuals learn. Learning to solve a new problem can be accelerated by generalizing known rules in the new context, but the impact of experience on solving problems where generalization cannot be applied remains unclear. To study the impact of experience on solving new problems that are distinct from previously learned tasks, we examined how rats learned a new spatial navigation task after having previously learned different sets of spatial navigation tasks. The new task differed from the previous tasks in spatial layout and navigation rule, and could not be solved by applying previously learned rules. We found that different experience histories did not impact task performance in the new task. However, by examining navigation choices made by rats, we found exploration patterns during the early stage of learning in the new task was dependent on experience history. We identified these behavioral differences by analyzing each rats navigation choices and by modeling their choice sequences with a modified distance dependent Chinese restaurant process. We further pinpointed the behavioral difference to sequential turn/no turn decisions made at choice points. Our results indicate that experience can influence problem-solving strategies when learning to solve new problems. Individuals with distinct experience histories can approach new problems from different starting points but converge on the same solution.

neuroscience↗

bioRxiv2023

Simultaneously-recorded cholinergic axons and cortical acetylcholine are highly correlated with pupil size and locomotion under spontaneous conditions

Even under spontaneous conditions and in the absence of changing environmental demands, awake animals alternate between increased or decreased periods of alertness. These changes in brain state can occur rapidly, on a timescale of seconds, and neuromodulators such as acetylcholine (ACh) are thought to play an important role in driving these spontaneous state transitions. Here, we perform the first simultaneous imaging of ACh sensors and GCaMP-expressing axons in vivo, to examine the spatiotemporal properties of cortical ACh activity and release during spontaneous changes in behavioral state. We observed a high correlation between simultaneously recorded basal forebrain axon activity and neuromodulator sensor fluorescence around periods of locomotion and pupil dilation. Consistent with volume transmission of ACh, increases in axon activity were accompanied by increases in local ACh levels that fell off with the distance from the nearest axon. GRAB-ACh fluorescence could be accurately predicted from axonal activity alone, providing the first validation that neuromodulator axon activity is a reliable proxy for nearby neuromodulator levels. Deconvolution of fluorescence traces allowed us to account for the kinetics of the GRAB-ACh sensor and emphasized the rapid clearance of ACh for smaller transients outside of running periods. Finally, we trained a predictive model of ACh fluctuations from the combination of pupil size and running speed; this model performed better than using either variable alone, and generalized well to unseen data. Overall, these results contribute to a growing understanding of the precise timing and spatial characteristics of cortical ACh during fast brain state transitions.

neuroscience↗

bioRxiv2023

Distinct eLPB ChAT projections for methamphetamine anxiety and relapse

Choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) send projections to PKC{delta}-positive (PKC{delta}+) neurons in lateral portion of central nucleus of amygdala (lCeAPKC{delta}) and oval portion of bed nucleus of the stria terminalis (ovBNSTPKC{delta}), forming eLPBChAT-lCeAPKC{delta} and eLPBChAT-ovBNSTPKC{delta} pathways. At least in part, the eLPBChAT neurons positively innervate lCeAPKC{delta} and ovBNSTPKC{delta} through regulating synaptic elements of presynaptic acetylcholine (Ach) release and postsynaptic nicotinic acetylcholine receptors (nAChRs). Methamphetamine (METH) withdrawal anxiety and METH-primed reinstatement of conditioned place preference (CPP) recruit eLPBChAT-lCeAPKC{delta} pathway and eLPBChAT-ovBNSTPKC{delta} pathway in male METH-exposed mice, respectively.

neuroscience↗

bioRxiv2023

Development of a computational model to inform environmental surveillance sampling plans for Salmonella enterica serovar Typhi in wastewater

Typhoid fever - an acute febrile disease caused by infection with the bacterium Salmonella enterica serotype Typhi (S. Typhi) - continues to be a leading cause of global morbidity and mortality, especially in developing countries with limited access to safe drinking water and adequate sanitation. Environmental surveillance, the process of detecting and enumerating disease-causing agents in wastewater, enables estimating disease prevalence and trends within a community and is a useful tool to monitor the circulation of typhoid fever in endemic regions. This study presents a computational model, which combines dynamic and probabilistic modeling techniques, to predict - on a spatial and temporal scale - the probability of detecting S. Typhi in a wastewater system. This model may be utilized in communities to inform environmental surveillance sampling plans and may provide useful insight into selecting appropriate sampling locations and times.

microbiology↗

bioRxiv2023

scATAnno: Automated Cell Type Annotation for single-cell ATAC-seq Data

Recent advances in single-cell epigenomic techniques have created a growing demand for scATAC-seq analysis. One key analysis task is to determine cell type identity based on the epigenetic data. We introduce scATAnno, a python package designed to automatically annotate scATAC-seq data using large-scale scATAC-seq reference atlases. This workflow generates the reference atlases from publicly available datasets enabling accurate cell type annotation by integrating query data with reference atlases, without the use of scRNA-seq data. To enhance annotation accuracy, we have incorporated KNN-based and weighted distance-based uncertainty scores to effectively detect cell populations within the query data that are distinct from all cell types in the reference data. We compare and benchmark scATAnno against 7 other published approaches for cell annotation and show superior performance in multiple data sets and metrics. We showcase the utility of scATAnno across multiple datasets, including peripheral blood mononuclear cell (PBMC), Triple Negative Breast Cancer (TNBC), and basal cell carcinoma (BCC), and demonstrate that scATAnno accurately annotates cell types across conditions. Overall, scATAnno is a useful tool for scATAC-seq reference building and cell type annotation in scATAC-seq data and can aid in the interpretation of new scATAC-seq datasets in complex biological systems.

bioinformatics↗

bioRxiv2023

Bioorthogonal photocatalytic quinone methide decaging for cell-cell interaction labeling

Cell-cell interactions (CCIs) play crucial roles in directing diverse biological processes in multicellular organisms, making the high-sensitivity and selectivity characterization of the diverse CCIs in high demand yet still challenging. We herein introduced a bioorthogonal photocatalytic quinone methide decaging-enabled cell-cell interaction labeling strategy (CAT-Cell) for sensitive and spatiotemporally resolved profiling of multitype CCIs. By adapting an optimized quinone methide probe for interacting cell labeling, we demonstrated the excellent capacity of CAT-Cell for capturing CCIs directed by various receptor-ligand pairs (e.g., CD40-CD40L, TCR-pMHC) and further showed its compatibility with tumor-specific targeting systems. Finally, we used CAT-Cell to detect cytotoxic cells (e.g., antigenspecific T cells, Natural Killer cells) in mouse models containing splenocyte mixtures and tumor samples. By leveraging the bioorthogonal photocatalytic decaging chemistry, CAT-Cell offers as a nongenetic, non-invasive and universal toolbox for profiling diverse CCIs under physiological-relevant settings.

biochemistry↗

bioRxiv2023

The characterisation of phytoene synthase-1 and 2, and 1-D-deoxy-xylulose 5-phosphate synthase genes from red chilli pepper (Capsicum annuum)

The red colouration of ripe chilli pepper fruit is due to the presence of the carotenoid capsanthin. 1-D-deoxy-xylulose 5-phosphate synthase (DXS) and phytoene synthase(s) (PSY) are influential biosynthetic steps in the carotenoid pathway. A panel of chilli accessions for varying fruit colour intensity revealed the correlation of carotenoid content with PSY and DXS transcript levels. The PSY and DXS genes were sequenced from high and low carotenoid genotypes to deduce potential allelic variation. PSY-1 and -2 showed tissue specific expression, with PSY-1and 2 expressed in chromoplast and chloroplast containing tissues, respectively. Protein modelling, phylogenetic analysis and transcription factor analysis was conducted to understand how the allelic variation identified could affect carotenoid biosynthesis and regulation, and subsequently colour intensity phenotype. A candidate mutation located in the transit peptide of the PSY-1 protein sequence was identified in the low colour intensity genotype. Within the promoter region of the DXS gene present in the high colour intensity genotype sequence variation was determined in the glyceraldehyde 3-phosphate binding motif (GAPF) of the promoter region. These data can be exploited to develop tools and resources for the breeding of high colour intensity chilli pepper fruit. Key policy highlightsUsing the molecular findings disclosed in this article the potential exists to develop molecular markers for the breeding varieties of chilli peppers with improved aesthetic consumer preference and nutritional attributes.

molecular biology↗

bioRxiv2021

Alkaliphilus flagellata sp. nov., Butyricicoccus intestinisimiae sp. nov., Clostridium mobile sp. nov., Clostridium simiarum sp. nov., Dysosmobacter acutus sp. nov., Paenibacillus brevis sp. nov., Peptoniphilus ovalis sp. nov., and Tissierella simiarum sp. nov., isolated from monkey feces

Non-human primates harbor diverse microbiomes in their guts. As a part of China Microbiome Initiatives, we cultivated and characterized the gut microbiome of cynomolgus monkeys (Macaca fascicularis). In this report, we communicate the characterization and taxonomy of 8 bacterial strains that were obtained from fecal samples of captive cynomolgus monkeys. The results revealed that they represented 8 novel bacterial species. The proposed names of the 8 novel species are Alkaliphilus flagellate (type strain MSJ-5T =CGMCC 1.45007T=KCTC 15974T), Butyricicoccus intestinisimiae MSJd-7T (type strain MSJd-7T =CGMCC 1.45013T =KCTC 25112T), Clostridium mobile (type strain MSJ-11T =CGMCC 1.45009T=KCTC 25065T), Clostridium simiarum (type strain MSJ-4T =CGMCC 1.45006T =KCTC 15975T), Dysosmobacter acutus (type strain MSJ-2T =CGMCC 1.32896T=KCTC 15976T), Paenibacillus brevis MSJ-6T (type strain MSJ-6T =CGMCC 1.45008T=KCTC 15973T), Peptoniphilus ovalis (type strain MSJ-1T =CGMCC 1.31770T=KCTC 15977T), and Tissierella simiarum (type strain MSJ-40T =CGMCC 1.45012T=KCTC 25071T).

microbiology↗

bioRxiv2021

Unraveling Fe(II)-oxidizing mechanisms in a facultative Fe(II) oxidizer Sideroxydans lithotrophicus ES-1 via culturing, transcriptomics, and RT-qPCR

Sideroxydans lithotrophicus ES-1 grows autotrophically either by Fe(II) oxidation or thiosulfate oxidation, in contrast to most other neutrophilic Fe(II)-oxidizing bacteria (FeOB) isolates. This provides a unique opportunity to explore the physiology of a facultative FeOB and constrain the genes specific to Fe(II) oxidation. We compared the growth of S. lithotrophicus ES-1 on Fe(II), thiosulfate, and both substrates together. While initial growth rates were similar, thiosulfate-grown cultures had higher yield with or without Fe(II) present, which may give ES-1 an advantage over obligate FeOB. To investigate the Fe(II) and S oxidation pathways, we conducted transcriptomics experiments, validated with RT-qPCR. We explored the long-term gene expression response at different growth phases (over days-week) and expression changes during a short-term switch from thiosulfate to Fe(II) (90 min). The dsr and sox sulfur oxidation genes were upregulated in thiosulfate cultures. The Fe(II) oxidase gene cyc2 was among the top expressed genes during both Fe(II) and thiosulfate oxidation, and addition of Fe(II) to thiosulfate-grown cells caused an increase in cyc2 expression. These results support the role of Cyc2 as the Fe(II) oxidase and suggest that ES-1 maintains readiness to oxidize Fe(II) even in the absence of Fe(II). We used gene expression profiles to further constrain the ES-1 Fe(II) oxidation pathway. Notably, among the most highly upregulated genes during Fe(II) oxidation were genes for alternative complex III, reverse electron transport and carbon fixation. This implies a direct connection between Fe(II) oxidation and carbon fixation, suggesting that CO2 is an important electron sink for Fe(II) oxidation. ImportanceNeutrophilic FeOB are increasingly observed in various environments, but knowledge of their ecophysiology and Fe(II) oxidation mechanisms is still relatively limited. Sideroxydans are widely observed in aquifers, wetlands, and sediments, and genome analysis suggests metabolic flexibility contributes to their success. The type strain ES-1 is unusual amongst neutrophilic FeOB isolates as it can grow on either Fe(II) or a non-Fe(II) substrate, thiosulfate. Almost all our knowledge of neutrophilic Fe(II) oxidation pathways comes from genome analyses, with some work on metatranscriptomes. This study used culture-based experiments to test the genes specific to Fe(II) oxidation in a facultative FeOB and refine our model of the Fe(II) oxidation pathway. We gained insight into how facultative FeOB like ES-1 connect Fe, S, and C biogeochemical cycling in the environment, and suggest a multi-gene indicator would improve understanding of Fe(II) oxidation activity in environments with facultative FeOB.

microbiology↗

bioRxiv2020

Oxidized LDL but not angiotensin II induces the interaction between LOX-1 and AT1 receptors

Oxidized low-density lipoprotein (Ox-LDL) can induce cardiac hypertrophy, but the mechanism is still unclear. Here we elucidate the role of angiotensin II (AngII) receptor (AT1-R) in Ox-LDL-induced cardiomycyte hypertrophy. Inhibition of Ox-LDL receptor LOX-1 and AT1-R rather than AngII abolished Ox-LDL-induced hypertrophic responses. Similar results were obtained from the heart of mice lacking endogenous Ang II and their cardiomyocytes. Ox-LDL but not AngII induced binding of LOX-1 to AT1-R, and the inhibition of LOX-1 or AT1-R rather than AngII abolished the association of these two receptors. Ox-LDL-induced ERKs phosphorylation in LOX-1 and AT1-R-overexpression cells and the binding of both receptors were suppressed by the mutants of LOX-1 (Lys266Ala/Lys267Ala) or AT1-R (Glu257Ala), however, the AT1-R mutant lacking Gq protein-coupling ability only abolished the ERKs phosphorylation. The phosphorylation of ERKs induced by Ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by Gq protein inhibitor but not by Jak2, Rac1 and RhoA inhibitors. Therefore, the direct interaction between LOX-1 and AT1-R and the downstream Gq protein activation are important mechanisms for Ox-LDL-but not AngII-induced cardiomyocyte hypertrophy.

cell biology↗

bioRxiv2020

CoBRA: Containerized Bioinformatics workflow for Reproducible ChIP/ATAC-seq Analysis - from differential peak calling to pathway analysis

ChIP-seq and ATAC-seq have become essential technologies used as effective methods of measuring protein-DNA interactions and chromatin accessibility. However, there is a need for a scalable and reproducible pipeline that incorporates correct normalization between samples, adjustment of copy number variations, and integration of new downstream analysis tools. Here we present CoBRA, a modularized computational workflow which quantifies ChIP and ATAC-seq peak regions and performs unsupervised and supervised analysis. CoBRA provides a comprehensive state-of-the-art ChIP and ATAC-seq analysis pipeline that is usable by scientists with limited computational experience. This enables researchers to gain rapid insight into protein-DNA interactions and chromatin accessibility through sample clustering, differential peak calling, motif enrichment, comparison of sites to a reference DB and pathway analysis. Code availability: https://bitbucket.org/cfce/cobra

bioinformatics↗

bioRxiv2020

Inducing highly physiologically relevant phenotypes of human vascular smooth muscle cells via 3D printing

Vascular smooth muscle cells (vSMCs) are one of the essential cell types in blood vessel walls. A significant vSMC phenotype characteristic is that they collectively wrap around the outer layer of the healthy blood vessels with spindle-like morphology and help maintain the vascular tones and regulate the blood flow. Both physiological and biomedical research are impeded by the standard 2D cell culture approaches which do not create in vivo like microenvironment. Here, we systematically investigated the vSMCs culturing within 3D printed geometrical constraints and on printed microfilaments. Based on these models, we demonstrate a simple bioprinting approach for fast manufacturing vessel architectures with micro-grooved surfaces for vSMCs alignment. We validated that the vSMCs cultured on the printed vessel with microfilaments (VWMF) present a more physiologically relevant morphological phenotype and gene expression profile, and they are considerably more active in wound healing and ischemia than conventional planarly cultured vSMCs.

bioengineering↗

bioRxiv2020

Isolation and Characterization of 2019-nCoV-like Coronavirus from Malayan Pangolins

The outbreak of 2019-nCoV in the central Chinese city of Wuhan at the end of 2019 poses unprecedent public health challenges to both China and the rest world1. The new coronavirus shares high sequence identity to SARS-CoV and a newly identified bat coronavirus2. While bats may be the reservoir host for various coronaviruses, whether 2019-nCoV has other hosts is still ambiguous. In this study, one coronavirus isolated from Malayan pangolins showed 100%, 98.2%, 96.7% and 90.4% amino acid identity with 2019-nCoV in the E, M, N and S genes, respectively. In particular, the receptor-binding domain of the S protein of the Pangolin-CoV is virtually identical to that of 2019-nCoV, with one amino acid difference. Comparison of available genomes suggests 2019-nCoV might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus. Infected pangolins showed clinical signs and histopathological changes, and the circulating antibodies reacted with the S protein of 2019-nCoV. The isolation of a coronavirus that is highly related to 2019-nCoV in the pangolins suggests that these animals have the potential to act as the intermediate host of 2019-nCoV. The newly identified coronavirus in the most-trafficked mammal could represent a continuous threat to public health if wildlife trade is not effectively controlled.

microbiology↗

bioRxiv2020

Compressive Big Data Analytics: An Ensemble Meta-Algorithm for High-dimensional Multisource Datasets

Health advances are contingent on continuous development of new methods and approaches to foster data driven discovery in the biomedical and clinical health sciences. Open-science offers hope for tackling some of the challenges associated with Big Data and team-based scientific discovery. Domain-independent reproducibility, area-specific replicability, curation, analysis, organization, management and sharing of health-related digital objects are critical components. This study expands the functionality and utility of an ensemble semi-supervised machine learning technique called Compressive Big Data Analytics (CBDA). Applied to high-dimensional data, CBDA identifies salient features and key biomarkers for reliable and reproducible forecasting of binary or multinomial outcomes. The method relies on iterative subsampling, combines function optimization and statistical inference, and generates ensemble predictions of observed univariate outcomes. In this manuscript, we extend the CBDA technique by (1) efficiently handling extremely large datasets, (2) generalizing the internal and external validation steps, (3) expanding the set of base-learners for joint ensemble prediction, (4) introduce an automated selection of CBDA specifications, and (5) provide mechanisms to assess CBDA convergence, evaluate the prediction accuracy, and measure result consistency. We validated the CBDA 2.0 technique using synthetic datasets as well as a population-wide census-like study, which grounds the mathematical models and the computational algorithm into translational health research settings. Specifically, we empirically validated the CBDA technique on a large-scale clinical study (UK Biobank), which includes imaging, cognitive, and clinical assessment data. The UK Biobank archive presents several difficult challenges related to the aggregation, harmonization, modeling, and interrogation of the information. These problems are related to the complex longitudinal structure, feature heterogeneity, multicollinearity, incongruency, and missingness, as well as violations of classical parametric assumptions that require novel health analytical approaches. Our results showcase the scalability, efficiency and potential of CBDA to compress complex data into structural information leading to derived knowledge and translational action. The results of the real case-study suggest new and exciting avenues of research in the context of identifying, tracking, and treating mental health and aging-related disorders. Following open-science principles, we share the entire end-to-end protocol, source-code, and results. This facilitates independent validation, result reproducibility, and team-based collaborative discovery.

bioinformatics↗

bioRxiv2019

Hierarchical Markov Random Field model captures spatial dependency in gene expression, demonstrating regulation via the 3D genome

AO_SCPLOWBSTRACTC_SCPLOWHiC technology has revealed many details about the eukaryotic genomes complex 3D architecture. It has been shown that the genome is separated into organizational structures which are associated with gene expression. However, to the best of our knowledge, no studies have quantitatively measured the level of gene expression in the context of the 3D genome. Here we present a novel model that integrates data from RNA-seq and HiC experiments, and determines how much of the variation in gene expression can be accounted for by the genes spatial locations. We used Poisson hierarchical Markov Random Field (PhiMRF), to estimate the level of spatial dependency among protein-coding genes in two different human cell lines. The inference of PhiMRF follows a Bayesian framework, and we introduce the Spatial Interaction Estimate (SIE) to measure the strength of spatial dependency in gene expression. We find that the quantitative expression of genes in some chromosomes show meaningful positive intra-chromosomal spatial dependency. Interestingly, the spatial dependency is much stronger than the dependency based on linear gene neighborhoods, suggesting that 3D chromosome structures such as chromatin loops and Topologically Associating Domains (TADs) are strongly associated with gene expression levels. In some chromosomes the spatial dependency in gene expression is only detectable when the spatial neighborhoods are confined within TADs, suggesting TAD boundaries serve as insulating barriers for spatial gene regulation in the genome. We also report high inter-chromosomal spatial correlations in the majority of chromosome pairs, as well as the whole genome. Some functional groups of genes show strong spatial dependency in gene expression as well, providing new insights into the regulation mechanisms of these molecular functions. This study both confirms and quantifies widespread spatial correlation in gene expression. We propose that, with the growing influx of HiC data complementing gene expression data, the use of spatial dependence should be an integral part of the toolkit in the computational analysis of the relationship between chromosome structure and gene expression.

bioinformatics↗