Biology subjects

Zhang, G.

Publications and source records attributed to Zhang, G..

At least 397 records · Page 22Linked to original sources

bioRxiv2020

Objective Extraction of Evoked Event-related Oscillations from Time-frequency Representation of Event-related Potentials

Evoked event-related oscillations (EROs) have been widely used to explore the mechanisms of brain activities for both normal people and neuropsychiatric disease patients. The selection of regions of evoked EROs tends to be subjectively based on the previous studies and the visual inspection of grand averaged time-frequency representations (TFRs) which causes some missing or redundant information. Meanwhile, the evoked EROs cannot be fully extracted via the conventional time-frequency analysis (TFA) method because they are sometimes overlapped with each other or with artifacts in time, frequency, and space domains to some extent. Hence, these shortcomings may pose some challenges to investigate the related neuronal processes. A data-driven approach was introduced to fill the gaps as below: extracting the temporal and spatial components of interest simultaneously by principal component analysis and Promax rotation and projecting them to the electrode field to correct their variance and polarity indeterminacy, calculating the TFRs of the back-projected components, and determining the regions of interest objectively using the edge detection algorithm. We performed this novel approach and the conventional TFA method in analyzing both a synthetic dataset and an actual ERP dataset in a two-factor simple gambling paradigm of waiting time (short/long) and feedback (loss/gain) separately. Synthetic dataset results indicated that N2-theta and P3-delta oscillations were detected using the proposed approach, but, by comparison, only one oscillation was obtained via the conventional TFA method. Furthermore, the actual ERP dataset results of P3-delta for our approach revealed that it was sensitive to the waiting time (which also was found in the previous reports) but not for that of the conventional TFA method. This study manifested that the proposed approach can objectively extract evoked EROs, which allows a better understanding of the modulations of the oscillatory responses.

neuroscience↗

bioRxiv2020

Haplotype-based heritability estimations reveal gestational duration as a maternal trait and fetal size measurements at birth as fetal traits in human pregnancy

AbstractGenotype-based approaches for the estimation of SNP-based narrow-sense heritability [Formula] have limited utility in pregnancy-related outcomes due to confounding by the shared alleles between mother and child. Here, we propose a haplotype-based approach to estimate the genetic variance attributable to three haplotypes - maternal transmitted [Formula], maternal non-transmitted [Formula] and paternal transmitted [Formula] in mother-child pairs. We show through extensive simulations that our haplotype-based approach outperforms the conventional and contemporary approaches for resolving the contribution of maternal and fetal effects, particularly when m1 and p1 have different effects in the offspring. We apply this approach to estimate the explicit and relative maternal-fetal genetic contribution to the phenotypic variance of gestational duration and gestational duration adjusted fetal size measurements at birth in 10,375 mother-child pairs. The results reveal that variance of gestational duration is mainly attributable to m1 and m2 ([Formula]= 17.3%, S. E. = 5.2%; [Formula] = 12.2%, S. E. = 5.2%; [Formula] = 0.0%, S. E. = 5.0%). In contrast, variance of fetal size measurements at birth are mainly attributable to m1 and p1 ([Formula] = 18.6 - 36.4%, [Formula] = 0.0 - 5.2% and [Formula] = 4.4 - 13.6%). Our results suggest that gestational duration and fetal size measurements are primarily genetically determined by the maternal and fetal genomes, respectively. In addition, a greater contribution of m1 as compared to m2 and p1 [Formula] to birth length and head circumference suggests a substantial influence of correlated maternal-fetal genetic effects on these traits. Our newly developed approach provides a direct and robust alternative for resolving explicit maternal and fetal genetic contributions to the phenotypic variance of pregnancy-related outcomes.

genetics↗

bioRxiv2020

Historical population declines prompted significant genomic erosion in the northern and southern white rhinoceros (Ceratotherium simum)

Large vertebrates are extremely sensitive to anthropogenic pressure, and their populations are declining fast. The white rhinoceros (Ceratotherium simum) is a paradigmatic case: this African megaherbivore suffered a remarkable population reduction in the last 150 years due to human activities. The two white rhinoceros subspecies, the northern (NWR) and the southern white rhinoceros (SWR), however, underwent opposite fates: the NWR vanished quickly after the onset of the decline, while the SWR recovered after a severe bottleneck. Such demographic events are predicted to have an erosive effect at the genomic level, in connection with the extirpation of diversity, and increased genetic drift and inbreeding. However there is currently little empirical data available that allows us to directly reconstruct the subtleties of such processes in light of distinct demographic histories. Therefore to assess these effects, we generated a whole-genome, temporal dataset consisting of 52 re-sequenced white rhinoceros genomes, that represents both subspecies at two time windows: before and during/after the bottleneck. Our data not only reveals previously unknown population substructure within both subspecies, but allowed us to quantify the genomic erosion undergone by both, with post-bottleneck white rhinoceroses harbouring significantly fewer heterozygous sites, and showing higher inbreeding coefficients than pre-bottleneck individuals. Moreover, the effective population size suffered a decrease of two and three orders of magnitude in the NWR and SWR respectively, due to the recent bottleneck. Our data therefore provides much needed empirical support for theoretical predictions about the genomic consequences of shrinking populations, information that is relevant for understanding the process of population extinction. Furthermore, our findings have the potential to inform management approaches for the conservation of the remaining white rhinoceroses.

evolutionary biology↗

bioRxiv2020

A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.

biochemistry↗

bioRxiv2020

Direct and specific assessment of axonal injury and spinal cord microenvironments using diffusion correlation imaging

We describe a practical two-dimensional (2D) diffusion MRI framework to deliver specificity and improve sensitivity to axonal injury in the spinal cord. This approach provides intravoxel distributions of correlations of water mobilities in orthogonal directions, revealing sub-voxel diffusion components. Here we use it to investigate water diffusivities along axial and radial orientations within spinal cord specimens with confirmed, tract-specific axonal injury. First, we show using transmission electron microscopy and immunohistochemistry that tract-specific axonal beading occurs following Wallerian degeneration in the cortico-spinal tract as direct sequelae to closed head injury. We demonstrate that although some voxel-averaged diffusion tensor imaging (DTI) metrics are sensitive to this axonal injury, they are non-specific, i.e., they do not reveal an underlying biophysical mechanism of injury. Then we employ 2D diffusion correlation imaging (DCI) to improve discrimination of different water microenvironments by measuring and mapping the joint water mobility distributions perpendicular and parallel to the spinal cord axis. We determine six distinct diffusion spectral components that differ according to their microscopic anisotropy and mobility. We show that at the injury site a highly anisotropic diffusion component completely disappears and instead becomes more isotropic. Based on these findings, an injury-specific MR image of the spinal cord was generated, and a radiological-pathological correlation with histological silver staining % area was performed. The resulting strong and significant correlation (r = 0.70, p < 0.0001) indicates the high specificity with which DCI detects injury-induced tissue alterations. We predict that the ability to selectively image microstructural changes following axonal injury in the spinal cord can be useful in clinical and research applications by enabling specific detection and increased sensitivity to injury-induced microstructural alterations. These results also encourage us to translate DCI to higher spatial dimensions to enable assessment of traumatic axonal injury, and possibly other diseases and disorders in the brain.

neuroscience↗

bioRxiv2020

IRIS: an accurate and efficient barcode calling tool for in situ sequencing

SummaryThe emerging in situ RNA sequencing technologies which can capture and amplify RNA within the original tissues provides efficient solution for producing spatial expression map from dozens to thousands of genes. Most of in situ RNA-seq strategies developed recently infer the expression patterns based on the fluorescence signals from the images taken during sequencing. However, an automate and convenient tool for decoding signals from image information is still absent. Here we present an easy-to-use software named IRIS to efficiently decode image signals from in situ sequencing into nucleotide sequences. This software can record the quality score and the spatial information of the sequencing signals. We also develop an interactive R shiny app named DAIBC for data visualization. IRIS is designed in modules so that it could be easily extended and compatible to new technologies. Availability and implementationIRIS and DAIBC are freely available under BSD 3-Clause License at: https://github.com/th00516/ISS_pyIRIS. Contactguojie.zhang@bio.ku.dk

bioinformatics↗

bioRxiv2020

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

genomics↗

bioRxiv2020

Dr AFC: Drug Repositioning Through Anti-Fibrosis Characteristic

Fibrosis is a key component in the pathogenic mechanism of many diseases. These diseases involving fibrosis may share common mechanisms, therapeutic targets and therefore, common intervention strategies and medicines may be applicable for these diseases. For this reason, deliberately introducing anti-fibrosis characteristics into modelling may lead to more success in drug repositioning. In this study, anti-fibrosis knowledge base was first built by collecting data from multiple resources. Both structural and biological profiles were derived from the knowledge base and used for constructing machine learning models including Structural Profile Prediction Model (SPPM) and Biological Profile Prediction Model (BPPM). Three external public data sets were employed for validation purpose and further exploration of potential repositioning drugs in wider chemical space. The resulting SPPM and BPPM models achieve area under the receiver operating characteristic curve (AUC) of 0.879 and 0.972 in the training set, and 0.814 and 0.874 in the testing set. Additionally, our results also demonstrate that substantial amount of multi-targeting natural products possess notable anti-fibrosis characteristics and might serve as encouraging candidates in fibrosis treatment and drug repositioning. To leverage our methodology and findings, we developed repositioning prediction platform, Drug Repositioning based on Anti-Fibrosis Characteristic (Dr AFC) that is freely accessible via https://www.biosino.org/drafc.

bioinformatics↗

bioRxiv2020

Transcriptomic and proteomic dynamics during metamorphosis of Pacific oyster Crassostrea gigas

Many marine invertebrate phyla are characterized by indirect development. These animals transit from planktonic larvae to benthic adults via settlement and metamorphosis, which contributes to the adaption to the marine environment. Studying the biological process of metamorphosis is thus a key to understand the origin and evolution of indirect development. Numerous studies have been conducted on the relationships of metamorphosis with the marine environment, microorganisms, as well as the neurohormones, however, little is known on the gene regulation network (GRN) dynamics during metamorphosis. Metamorphosis competent pediveliger of Pacific oyster Crassostrea gigas was assayed in this study. By identifying genes enriched in competent pediveliger and early spat, as well as pediveligers treated with epinephrine, the dynamics of genes and proteins was examined with transcriptomics and proteomics methods. The results indicated significantly different gene regulation networks before, during, and post metamorphosis. Genes encoding membrane integrated receptors and related to the remodeling of the nervous system were upregulated before the initiation of metamorphosis. Massive biogenesis, e.g., various enzymes and structural proteins, occurred during metamorphosis. Correspondingly, the protein synthesis system was comprehensively activated after epinephrine stimulation. Hierarchical downstream gene networks were also stimulated, where some transcription factors showed different temporal response patterns, including some important Homeobox, basic helix-loop-helix factors and nuclear receptors. Nuclear receptors, as well as their retinoic acid receptor partners, should play critical roles during the oyster metamorphosis, although they may not be responsible for the initiation process. Enriched genes in early spat were mainly related to environmental stress responses, indicating the GRN complexity of the transition stage during oyster metamorphosis.View Full Text

zoology↗

bioRxiv2020

The first-in-class peptide binder to the SARS-CoV-2 spike protein

Coronavirus disease 19 (COVID-19) is an emerging global health crisis. With over 7 million confirmed cases to date, this pandemic continues to expand, spurring research to discover vaccines and therapies. SARS-CoV-2 is the novel coronavirus responsible for this disease. It initiates entry into human cells by binding to angiotensin-converting enzyme 2 (ACE2) via the receptor binding domain (RBD) of its spike protein (S). Disrupting the SARS-CoV-2-RBD binding to ACE2 with designer drugs has the potential to inhibit the virus from entering human cells, presenting a new modality for therapeutic intervention. Peptide-based binders are an attractive solution to inhibit the RBD-ACE2 interaction by adequately covering the extended protein contact interface. Using molecular dynamics simulations based on the recently solved cryo-EM structure of ACE2 in complex with SARS-CoV-2-RBD, we observed that the ACE2 peptidase domain (PD) 1 helix is important for binding SARS-CoV-2-RBD. Using automated fast-flow peptide synthesis, we chemically synthesized a 23-mer peptide fragment of the ACE2 PD 1 helix (SBP1) composed entirely of proteinogenic amino acids. Chemical synthesis of SBP1 was complete in 1.5 hours, and after work up and isolation >20 milligrams of pure material was obtained. Bio-layer interferometry (BLI) revealed that SBP1 associates with micromolar affinity to insect-derived SARS-CoV-2-RBD protein obtained from Sino Biological. Association of SBP1 was not observed to an appreciable extent to HEK cell-expressed SARS-CoV-2-RBD proteins and insect-derived variants acquired from other vendors. Moreover, competitive BLI assays showed SBP1 does not outcompete ACE2 binding to Sino Biological insect-derived SARS-CoV-2-RBD. Further investigations are ongoing to gain insight into the molecular and structural determinants of the variable binding behavior to different SARS-CoV-2-RBD protein variants.

bioengineering↗

bioRxiv2020

RBD mutations from circulating SARS-CoV-2 strains enhance the structure stability and infectivity of the spike protein

The current global pandemic of COVID-19 is caused by a novel coronavirus SARS-CoV-2. The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring mutations in the RBD during the early transmission phase have altered the receptor binding affinity and infectivity, firstly we analyzed in silico the binding dynamics between mutated SARS-CoV-2 RBDs and the human ACE2 receptor. Among 32,123 genomes of SARS-CoV-2 isolates (January through March, 2020), 302 non-synonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations. The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding ELISA, surface plasmon resonance, and pseudotyped virus assays. Genome phylogenetic analysis of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F + D614G) which emerged later and formed a distinct sub-cluster. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of SARS-CoV-2 under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. ImportanceA novel coronavirus SARS-CoV-2 has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether the mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and caused them more infectious, should be paid more attentions to. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase that have increased human ACE2 receptor binding affinity and infectivity. The RBD mutation analysis provides insights into SARS-CoV-2 evolution. The continuous surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is important and necessary, particularly when the direct correlation between the virus variations and vaccine effectiveness is underdetermined during the sustained COVID-19 pandemic.

microbiology↗

bioRxiv2020

Ancient and modern genomes reveal microsatellites maintain a dynamic equilibrium through deep time

Microsatellites are widely used in population genetics, but their evolutionary dynamics remain poorly understood. It is unclear whether microsatellite loci drift in length over time. We identify more than 27 million microsatellites using a novel and unique dataset of modern and ancient Adelie penguin genomes along with data from 63 published chordate genomes. We investigate microsatellite evolutionary dynamics over two time scales: one based on the Adelie penguin samples dating to approximately 46.5 kya, the other dating to the diversification of chordates more than 500 Mya. We show that the process of microsatellite allele length evolution is at dynamic equilibrium; while there is length polymorphism among individuals, the length distribution for a given locus remains stable. Many microsatellites persist over very long time scales, particularly in exons and regulatory sequence. These often retain length variability, suggesting that they may play a role in the maintenance of evolutionary plasticity.

evolutionary biology↗

bioRxiv2020

Circ_0005962 functions as an oncogene to aggravate non-small cell lung cancer progression via circ_0005962/miR-382-5p/PDK4 regulatory network

Non-small cell lung cancer (NSCLC) is a leading threat to human lives with high incidence and mortality. Circular RNAs (circRNAs) were reported to play important roles in human cancers. The purpose of this study was to investigate the role of circ_0005962 and explore the underlying functional mechanisms. The expression of circ_0005962, miR-382-5p and pyruvate dehydrogenase kinase 4 (PDK4) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation and cell apoptosis were assessed by cell counting kit-8 (CCK-8) assay and flow cytometry assay, respectively. The protein levels of Beclin 1, light chain3 (LC3-II/LC3-I), PDK4, Cleaved Caspase 3 (C-caspase 3) and proliferating cell nuclear antigen (PCNA) were examined using western blot analysis. Glycolysis was determined according to the levels of glucose consumption and lactate production. The interaction between miR-382-5p and circ_0005962 or PDK4 was predicted by the online tool CircInteractome or starbase and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenograft model was constructed to investigate the role of circ_0005962 in vivo. circ_0005962 expressed with a high level in NSCLC tissues and cells. Circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but promoted apoptosis in NSCLC cells. MiR-382-5p was targeted by circ_0005962, and its inhibition reversed the role of circ_0005962 knockdown. Besides, PDK4, a target of miR-382-5p, was regulated by circ_0005962 through miR-382-5p, and its overexpression abolished the effects of miR-382-5p reintroduction. Circ_0005962 knockdown suppressed tumor growth in vivo. Circ_0005962 knockdown restrained cell proliferation, autophagy, and glycolysis but stimulated apoptosis through modulating the circ_0005962/miR-382-5p/PDK4 axis. Our study broadened the insights into understanding the mechanism of NSCLC progression.

cell biology↗

bioRxiv2020

A draft genome assembly of the eastern banjo frog Limnodynastes dumerilii dumerilii (Anura: Limnodynastidae)

Amphibian genomes are usually challenging to assemble due to large genome size and high repeat content. The Limnodynastidae is a family of frogs native to Australia, Tasmania and New Guinea. As an anuran lineage that successfully diversified on the Australian continent, it represents an important lineage in the amphibian tree of life but lacks reference genomes. Here we sequenced and annotated the genome of the eastern banjo frog Limnodynastes dumerilii dumerilii to fill this gap. The total length of the genome assembly is 2.38 Gb with a scaffold N50 of 285.9 kb. We identified 1.21 Gb of non-redundant sequences as repetitive elements and annotated 24,548 protein-coding genes in the assembly. BUSCO assessment indicated that more than 94% of the expected vertebrate genes were present in the genome assembly and the gene set. We anticipate that this annotated genome assembly will advance the future study of anuran phylogeny and amphibian genome evolution.

genomics↗

bioRxiv2020

Tracing the origin of a new organ by inferring the genetic basis of rumen evolution

The rumen is the hallmark organ of ruminants and hosts a diverse ecosystem of microorganisms that facilitates efficient digestion of plant fibers. We used 897 transcriptomes from three Cetartiodactyla lineages: ruminants, camels and cetaceans, as well as data from ruminant comparative genomics and functional assays to explore the genetic basis of rumen origin and evolution. Comparative analyses reveal that the rumen and the first-chamber stomachs of camels and cetaceans shared a common tissue origin from the esophagus. The rumen recruited genes from other tissues/organs and up-regulated many esophagus genes to aquire functional innovations involving epithelium absorption, improvement of the ketone body metabolism and regulation of microbial community. These innovations involve such genetic changes as ruminant-specific conserved elements, newly evolved genes and positively selected genes. Our in vitro experiements validate the functions of one enhancer, one positively selected gene and two newly evolved antibacterial genes. Our study provides novel insights into the origin and evolution of a complex organ.

evolutionary biology↗

bioRxiv2020

The construction and application of a new 17-plex Y-STR system using universal fluorescent PCR

Y-chromosomal short tandem repeat (Y-STR) polymorphisms are useful in forensic identification, population genetics and human structures. However, the current Y-STR systems are limited in discriminating distant relatives in a family with a low discrimination power. Increasing the capacity of detecting Y chromosomal polymorphisms will drastically narrow down the matching number of genealogy populations or pedigrees. In this study, we developed a system containing 17 Y-STRs that are complementary to the current commercially available Y-STR kits. This system was constructed by multiplex PCR with expected sizes of 126-400 bp labeled by different fluorescence molecules (DYS715, DYS709, DYS716, DYS713 and DYS607 labeled by FAM; DYS718, DYS723, DYS708 and DYS714 labeled by JOE; DYS712, DYS717, DYS721 and DYS605 labeled by TAMRA; and DYS719, DYS726, DYS598 and DYS722 labeled by ROX). The system was extensively tested for sensitivity, male specificity, species specificity, mixture, population genetics and mutation rates following the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines. The genetic data were obtained from eight populations with a total of 1260 individuals. Our results showed that all the 17 Y-STRs are human- and male-specific and include only one copy of the Y-chromosome. The 17 Y-STR system detects 143 alleles and has a high discrimination power (0.996031746). Mutation rates were different among the 17 Y-STRs, ranging from 0.30% to 3.03%. In conclusion, our study provides a robust, sensitive and cost-effective genotyping method for human identification, which will be beneficial for narrowing the search scope when applied to genealogy searching with the Y-STR DNA databank.

genetics↗

bioRxiv2020

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↗

bioRxiv2020

LncRNA GAS5 attenuates fibroblast activation through inhiting Smad3-mediated myofibroblast marker gene expression.

Transforming Growth Factor {beta} (TGF-{beta})-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (lncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-{beta}-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-{beta} and in resident fibroblasts from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-{beta}-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound Smad3 and promoted Smad3 binding to PPM1A, a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-{beta}-treated fibroblasts. In addition, GAS5 inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGF-{beta}/Smad3 signaling, which provides a rationale for an lncRNA-based therapy to treat fibrotic diseases.

molecular biology↗