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Jia, Z.

Publications and source records attributed to Jia, Z..

At least 91 records · Page 5Linked to original sources

Structural variant selection for high-altitude adaptation using single-molecule long-read sequencing

Structural variants (SVs) can be important drivers of human adaptation with strong effects, but previous studies have focused primarily on common variants with weak effects. Here, we used large-scale single-molecule long-read sequencing of 320 Tibetan and Han samples, to show that SVs are key drivers of selection under high-altitude adaptation. We expand the landscape of global SVs, apply robust models of selection and population differentiation combining SVs, SNPs and InDels, and use epigenomic analyses to predict driver enhancers, target genes, upstream regulators, and biological functions, which we validate using enhancer reporter and DNA pull-down assays. We reveal diverse Tibetan-specific SVs affecting the cis- and trans-regulatory circuitry of diverse biological functions, including hypoxia response, energy metabolism, lung function, etc. Our study greatly expands the global SV landscape, reveals the central role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles that SVs can play in human biology.

genomics↗

Genomics-informed insights into microbial degradation of N,N-dimethylformamide

Effective degradation of N,N-Dimethylformamide (DMF), an important industrial waste product, is challenging as only few bacterial isolates are known to be capable of degrading DMF. Aerobic remediation of DMF has typically been used, whereas anoxic remediation attempts are recently made, using nitrate as one electron acceptor, and ideally include methane as a byproduct. Here, we analyzed 20,762 complete genomes and 28 constructed draft genomes for the genes associated with DMF degradation. We identified 952 genomes that harbor genes involved in DMF degradation, expanding the known diversity of prokaryotes with these metabolic capabilities. Our findings suggest acquisition of DMF-degrading gene via plasmids are important in the order Rhizobiales and genus Paracoccus, but not in most other lineages. Degradation pathway analysis reveals that most putative DMF degraders using aerobic Pathway I will accumulate methylamine intermediate, while members of Paracoccus, Rhodococcus, Achromobacter, and Pseudomonas could potentially mineralize DMF completely under aerobic conditions. The aerobic DMF degradation via Pathway II is more common than thought and is primarily present in -and {beta}-Proteobacteria and Actinobacteria. Most putative DMF degraders could grow with nitrate anaerobically (Pathway III), however, genes for the use of methyl-CoM to produce methane were not found. These analyses suggest that microbial consortia could be more advantageous in DMF degradation than pure culture, particularly for methane production under the anaerobic condition. The identified genomes and plasmids form an important foundation for optimizing bioremediation of DMF-containing wastewaters. ImportanceDMF is extensively used as a solvent in industries, and is classified as a probable carcinogen. DMF is a refractory compound resistant to degradation, and until now, only few bacterial isolates have been reported to degrade DMF. To achieve effective microbial degradation of DMF from wastewater, it is necessary to identify genomic diversity with the potential to degrade DMF and characterize the genes involved in two aerobic degradation pathways and potential anaerobic degradation for methane production. A wide diversity of organisms has the potential to degrade DMF. Plasmid-mediated degradation of DMF is important for Rhizobiales and Paracoccus. Most DMF degraders could grow anaerobically with nitrate as electron acceptor, while co-cultures are required to complete intermediate methanogenesis for methane production. This is the first genomics-based global investigation into DMF degradation pathways. The genomic database generated by this study provides an important foundation for the bioremediation of DMF in industrial waste waters. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/435917v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@e46e1dorg.highwire.dtl.DTLVardef@f93887org.highwire.dtl.DTLVardef@1ee5ce8org.highwire.dtl.DTLVardef@15a529_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

Mechanism of REST/NRSF Regulation of Clustered Protocadherin Alpha Genes

Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5-1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDH genes. Thus, REST/NRSF represses PCDH gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.

molecular biology↗

The jasmine (Jasminum sambac) genome and flower fragrances

Jasminum sambac, a world-renowned plant appreciated for its exceptional flower fragrance, is of cultural and economic importance. However, the genetic basis of its fragrance is largely unknown. Here, we present the first de novo genome of J. sambac with 550.12 Mb (scaffold N50 = 40.1 Mb) assembled into 13 pseudochromosomes. Terpene synthase genes associated with flower fragrance are significantly amplified in the form of gene clusters through tandem duplications in the genome. Eleven homolog genes within the SABATH super-family were identified as related to phenylpropanoid/benzenoid compounds. Several key genes regulating jasmonate biosynthesis were duplicated causing increased copy numbers. Furthermore, multi-omics analyses identified various aromatic compounds and the key genes involved in fragrance biosynthesis pathways. Our genome of J. sambac offers a basic genetic resource for studying floral scent biosynthesis and provides an essential foundation for functional genomic research and variety improvements in Jasminum.

plant biology↗

Integrative Transcriptomic Analysis Reveals the Immune Mechanism for A CyHV-3-Resistant Common Carp Strain

Anti-disease breeding is becoming the most promising solution to cyprinid herpesvirus-3 (CyHV-3) infection, the major threat to common carp aquaculture. Virus challenging studies suggested that a breeding strain of common carp is resistant to this disease. This study illustrates the immune mechanisms involved in anti-CyHV-3 ability. An integrative analysis of the protein-coding genes and long non-coding RNAs (lncRNAs) using transcriptomic data was performed. Tissues from the head kidney of common carp were extracted at day 0 (the healthy control) and day 7 after CyHV-3 infection (the survivors), and used to analyze the transcriptome through both Illumina and PacBio sequencing. Following analysis of the GO terms and KEGG pathways involved, the immune-related terms and pathways were merged. In order to dig out details in the immune aspect, The DEGs were filtered using the current common carp immune gene library. Immune gene categories and their corresponding genes in different comparison groups were revealed. Also, the immunological Gene Ontology terms for lncRNA modulation were retained. The weighted gene co-XSexpression network analysis was used to reveal the regulation of immune genes by lncRNA. The results demonstrated that the breeding carp strain develops marked resistance to CyHV-3 through a specific innate immune mechanism. The featured biological processes were autophagy, phagocytosis, cytotoxicity, and virus blockage by lectins and MUC3. Moreover, the immune suppressive signals, such as suppression of IL21R on STAT3, PI3K mediated inhibition on inflammation by dopamine upon infection, as well as the inhibition of NLRC3 on STING during a steady state. Possible susceptible factors for CyHV-3, such as ITGB1, TLR18, and CCL4, were also revealed from the non-breeding strain. The results of this study also suggested that Nramp and PAI regulated by LncRNA could facilitate virus infection and proliferation for infected cells respectively, while T cell leukemia homeobox 3 (TLX3) as well as galectin 3 function by lncRNA may play a role in the resistance mechanism. Therefore, immune factors that are immunogenetically insensitive or susceptible to CyHV-3 infection have been revealed.

immunology↗

Resuscitation of soil microbiota after > 70-years of desiccation

The abundance and diversity of bacteria in 24 historical soil samples under air-dried storage conditions for more than 70 years were assessed by quantification and high-throughput sequencing analysis of 16S rRNA genes. All soils contained a measurable abundance of bacteria varying from 103 to 108 per gram of soil and contrasting community compositions were observed in different background soils, suggesting that the bacteria detected were indigenous to the soil. Following a 4-week soil rewetting event, the bacterial abundance significantly increased in soils, indicating strong adaptation of soil bacteria to extreme osmotic change and high resuscitation potential of some bacteria over long periods of desiccation. Paenibacillus, Cohnella and two unclassified Bacillales genera within the phylum Firmicutes represented the most ubiquitously active taxa, which showed growth in the highest number of soils ([≥]12 soils), while genera Tumebacillus, Alicyclobacillus and Brevibacillus in the phylum Firmicutes displayed the highest growth rates in soils (with >1000-fold average increase) following rewetting. Additionally, some Actinobacteria and Proteobacteria genera showed relatively high activity following rewetting, suggesting that the resilience to long-term desiccation and rewetting is a common trait across phylogenetically divergent microbes. The present study thus demonstrated that diversified groups of microbes are present and potentially active in historically desiccated soils, which might be of importance in the context of microbial ecology.

microbiology↗

CancerMIRNome: a web server for interactive analysis and visualization of cancer miRNome data

MicroRNAs (miRNAs), which play critical roles in gene regulatory networks, have emerged as promising diagnostic and prognostic biomarkers for human cancer. In particular, circulating miRNAs that are secreted into circulation exist in remarkably stable forms, and have enormous potential to be leveraged as non-invasive biomarkers for early cancer detection. Novel and user-friendly tools are desperately needed to facilitate data mining of the vast amount of miRNA expression data from The Cancer Genome Atlas (TCGA) and large-scale circulating miRNA profiling studies. To fill this void, we developed CancerMIRNome, a comprehensive database for the interactive analysis and visualization of miRNA expression profiles based on 10,998 samples from 33 TCGA projects and 21,993 samples from 40 public circulating miRNome datasets. A series of cutting-edge bioinformatics tools and machine learning algorithms have been packaged in CancerMIRNome, allowing for the pan-cancer analysis of a miRNA of interest across multiple cancer types and the comprehensive analysis of miRNome profiles to identify dysregulated miRNAs and develop diagnostic or prognostic signatures. The data analysis and visualization modules will greatly facilitate the exploit of the valuable resources and promote translational application of miRNA biomarkers in cancer. The CancerMIRNome database is publicly available at http://bioinfo.jialab-ucr.org/CancerMIRNome.

bioinformatics↗

FlyWire: Online community for whole-brain connectomics

Due to advances in automated image acquisition and analysis, new whole-brain connectomes beyond C. elegans are finally on the horizon. Proofreading of whole-brain automated reconstructions will require many person-years of effort, due to the huge volumes of data involved. Here we present FlyWire, an online community for proofreading neural circuits in a fly brain, and explain how its computational and social structures are organized to scale up to whole-brain connectomics. Browser-based 3D interactive segmentation by collaborative editing of a spatially chunked supervoxel graph makes it possible to distribute proofreading to individuals located virtually anywhere in the world. Information in the edit history is programmatically accessible for a variety of uses such as estimating proofreading accuracy or building incentive systems. An open community accelerates proofreading by recruiting more participants, and accelerates scientific discovery by requiring information sharing. We demonstrate how FlyWire enables circuit analysis by reconstructing and analysing the connectome of mechanosensory neurons.

neuroscience↗

PTEN Inhibition Ameliorates Muscle Degeneration and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is caused by mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting and loss of mobility, ultimately cardiorespiratory failure and premature death. Here we report that skeletal muscle-specific knockout (KO) of Phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidences. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and improves grip strength and exercise performance of mdx mice. Pten KO also reduces fibrosis and inflammation; and ameliorates muscle pathology in mdx mice. Moreover, we found that Pten KO upregulates extracellular matrix and basement membrane components positively correlated to wound healing, but suppresses negative regulators of wound healing and lipid biosynthesis; and restores the integrity of muscle basement membrane in mdx mice. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our finding provides evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD.

developmental biology↗

PAK3 controls the tangential to radial migration switch of cortical interneurons by coordinating changes in cell shape and polarity

During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate where they contribute to cortical circuits. Migrating interneurons express PAK3, a p21-activated kinase that switches between active and inactive states and controls interneuron migration by unknown mechanism(s). Here we examined the role of the kinase activity of PAK3 to regulate the migration of cortical interneurons. We showed that interneurons expressing a constitutively active PAK3 mutant (PAK3-ca) oriented preferentially radially in the cortex, extended short leading processes and exhibited unstable polarity. On the contrary, interneurons expressing an inactive PAK3 mutant (PAK3-kd for kinase dead) extended branched leading processes, showed directed nuclear movements and remained in the tangential pathways. Results showed that PAK3 kinase activity controls the switch between the tangential and radial modes of migration of cortical interneurons and identified myosin 2B as an effector of this switch.

developmental biology↗

Structural insight into outer membrane asymmetry maintenance of Gram-negative bacteria by the phospholipid transporter MlaFEDB

The asymmetric phospholipid outer membrane (OM) of Gram-negative bacteria serves as the first line of defense against cytotoxic substances such as antibiotics. The Mla pathway is known to maintain the lipid asymmetry of the OM by transporting phospholipids between the inner and outer membranes. Six Mla proteins MlaFEDBCA are involved, with the ABC transporter MlaFEDB acts through a mechanism yet to be elucidated. Here we determine cryo-EM structures of MlaFEDB in apo, phospholipid-, ADP- or AMP-PNP-bound state to 3.3-3.75 [A] resolution and establish a proteoliposome-based transport system containing MlaFEDB, MlaC and MlaA/OmpF to reveal the transport direction of phospholipids. Mutagenetic in vitro transport assays and in vivo sensitivity assays reveal functional residues which recognize and transport phospholipids as well as regulate the activity and structural stability of the MlaFEDB complex. Our work provides molecular basis for understanding the mechanism of the Mla pathway which could be targeted for antimicrobial drug development.

biochemistry↗

Extended Application of Genomic Selection to Screen Multi-Omics Data for Prognostic Signatures of Prostate Cancer

Prognostic tests using expression profiles of several dozen genes help provide treatment choices for prostate cancer (PCa). However, these tests require improvement to meet the clinical need for resolving overtreatment which continues to be a pervasive problem in PCa management. Genomic selection (GS) methodology, which utilizes whole-genome markers to predict agronomic traits, was adopted in this study for PCa prognosis. We leveraged The Cancer Genome Atlas (TCGA) database to evaluate the prediction performance of six GS methods and seven omics data combinations, which showed that the Best Linear Unbiased Prediction (BLUP) model outperformed the other methods regarding predictability and computational efficiency. Leveraging the BLUP-HAT method, an accelerated version of BLUP, we demonstrated that using expression data of a large number of disease-relevant genes and with an integration of other omics data (i.e., miRNAs) significantly increased outcome predictability when compared with panels consisting of small numbers of genes. Finally, we developed a novel stepwise forward selection BLUP-HAT method to facilitate searching multi-omics data for predictor variables with prognostic potential. The new method was applied to the TCGA data to derive mRNA and miRNA expression signatures for predicting relapse-free survival of PCa, which were validated in six independent cohorts. This is a transdisciplinary adoption of the highly efficient BLUP-HAT method and its derived algorithms to analyze multi-omics data for PCa prognosis. The results demonstrated the efficacy and robustness of the new methodology in developing prognostic models in PCa, suggesting a potential utility in managing other types of cancer.

bioinformatics↗

Specific PIP2 Binding Promotes Calcium Activation of TMEM16A Chloride Channels

TMEM16A is a widely expressed Ca2+-activated Cl- channel that regulates crucial physiological functions including fluid secretion, neuronal excitability, and smooth muscle contraction. There is a critical need to understand the molecular mechanisms of TMEM16A gating and regulation. However, high-resolution TMEM16A structures have failed to reveal an activated state with unobstructed permeation pathway even with saturating Ca2+. This has been attributed to the requirement of PIP2 for preventing TMEM16A desensitization. Here, we show that specific binding PIP2 to TMEM16A can lead to spontaneous opening of the permeation pathway in the Ca2+-bound state. The predicted activated state is highly consistent with a wide range of mutagenesis and functional data. It yields a maximal Cl- conductance of ~1 pS, similar to experimental estimates, and recapitulates the selectivity of larger SCN- over Cl-. The resulting molecular mechanism of activation provides a basis for understanding the interplay of multiple signals in controlling TMEM16A channel function.

biochemistry↗

Nonspecific membrane interactions can modulate BK channel activation

Large-conductance potassium (BK) channels are transmembrane (TM) proteins that can be synergistically and independently activated by membrane voltage and intracellular Ca2+. The only covalent connection between the cytosolic Ca2+ sensing domain and the TM pore and voltage sensing domains is a 15-residue "C-linker". To determine the linker's role in BK activation, we designed a series of linker sequence scrambling mutants to suppress potential complex interplay of specific interactions with the rest of the protein. The results revealed a surprising sensitivity of BK activation to the linker sequence. Combing atomistic simulations and further mutagenesis experiments, we demonstrated that nonspecific interactions of the linker with membrane alone could directly modulate BK activation. The C-linker thus plays more direct roles in mediating allosteric coupling between BK domains than previously assumed. Our results also suggest that covalent linkers could directly modulate TM protein function and should be considered an integral component of the sensing apparatus.

biophysics↗

The dark side of amyloid aggregation: Exploring the productive and non-productive pathways with multi-scale modeling

Atomistic description of protein fibril formation has remained prohibitive due to the complexity and long timescales of the conformational search problem. Here, we develop a multi-scale approach that combines a large number of atomistic molecular dynamics simulations in explicit solvent to derive Markov State Models (MSMs) for simulation of fibril growth. The search for the in-registered fully bound fibril state is modeled as a random walk on a rugged 2D energy landscape along enumerated {beta}-sheet registry and hydrogen bonding states, whereas interconversions among nonspecific bound states and between nonspecific and hydrogen-bounded states are derived from kinetic clustering analysis. The reversible association/dissociation of an incoming peptide and overall growth kinetics are then computed from MSM trajectories. This approach is applied to derive a comprehensive description of fibril elongation of wild-type A{beta}16-22 and how it is modulated by phenylalanine to cyclohexane (CHA) mutations. The resulting models recapitulate the experimental observation that mutants CHA19 and CHA1920 accelerate fibril elongation, but have a relatively minor effect on the critical concentration for fibril growth. Importantly, the kinetic consequences of mutations arise from a complex perturbation of the network of productive and non-productive pathways of fibril grown. This is consistent with the expectation that non-functional states will not have evolved efficient folding pathways and, therefore, will require a random search of configuration space. This study highlights the importance of describing the complete energy landscape when studying the elongation mechanism and kinetics of protein fibrils.

biophysics↗

New mechanism-based inhibitors of aspartate transcarbamoylase for anticancer drug development

Aspartate transcarbamoylase (ATCase) is a key enzyme which regulates and catalyzes the second step of de novo pyrimidine synthesis in all organisms. E. coli ATCase is a prototypic enzyme regulated by both product feedback and substrate cooperativity, whereas human ATCase is a potential anticancer target. Through structural and biochemical analyses, we revealed that R167/130s loop region in ATCase serves as a gatekeeper for the active site, playing a new and unappreciated role in feedback regulation. Based on virtual compound screening simultaneously targeting the new regulatory region and active site of human ATCase, two compounds were identified to exhibit strong inhibition of ATCase activity, proliferation of multiple cancer cell lines, and growth of xenograft tumors. Our work has not only revealed a previously unknown regulatory region of ATCase that helps explain feedback regulation, but also successfully guided the identification of new ATCase inhibitors for anticancer drug development using a dual-targeting strategy.

cancer biology↗

Tandem Directional CTCF Sites Balance Protocadherin Promoter Usage

CTCF is a key insulator-binding protein and mammalian genomes contain numerous CTCF-binding sites (CBSs), many of which are organized in tandem arrays. Here we provide direct evidence that CBSs, if located between enhancers and promoters in the Pcdh and {beta}-globin clusters, function as an enhancer-blocking insulator by forming distinct directional chromatin loops, regardless whether enhancers contain CBS or not. Moreover, computational simulation and experimental capture revealed balanced promoter usage in cell populations and stochastic monoallelic expression in single cells by large arrays of tandem variable CBSs. Finally, gene expression levels are negatively correlated with CBS insulators located between enhancers and promoters on a genome-wide scale. Thus, single CBS insulators ensure proper enhancer insulation and promoter activation while tandem-arrayed CBS insulators determine balanced promoter usage. This finding has interesting implications on the role of topological insulators in 3D genome folding and developmental gene regulation.

molecular biology↗

Identification of seed coat pattern trait QTL and a description of seed coat development in cowpea (Vigna unguiculata Walp.)

The appearance of the seed is an important aspect of consumer preference for cowpea (Vigna unguiculata [L.] Walp.). Seed coat pattern in cowpea has been a subject of study for over a century. This study makes use of newly available resources, including mapping populations, a reference genome and additional genome assemblies, and a high-density single nucleotide polymorphism genotyping platform, to map various seed coat pattern traits to three loci, concurrent with the Color Factor (C), Watson (W), and Holstein (H) factors identified previously. Several gene models encoding proteins involved in regulating the later stages of the flavonoid biosynthesis pathway have been identified as candidate genes, including a basic helix-loop-helix gene (Vigun07g110700) for the C locus, a WD-repeat gene (Vigun09g139900) for the W locus and an E3 ubiquitin ligase gene (Vigun10g163900) for the H locus. A model of seed coat development, consisting of six distinct stages, is described to explain some of the observed pattern phenotypes.

genetics↗