Biology subjects

Jiang, X.

Publications and source records attributed to Jiang, X..

At least 235 records · Page 13Linked to original sources

bioRxiv2023

ScopeViewer: A Browser-Based Solution for Visualizing Spatial Transcriptomics Data

MotivationSpatial transcriptomics (ST) enables a high-resolution interrogation of molecular characteristics within specific spatial contexts and tissue morphology. Despite its potential, visualization of ST data is a challenging task due to the complexities in handling, sharing and visualizing large image datasets together with molecular information. ResultsWe introduce ScopeViewer, a browser-based software designed to overcome these challenges. ScopeViewer offers the following functionalities: (1) It visualizes large image data and associated annotations at various zoom levels, allowing for intricate exploration of the data; (2) It enables dual interactive viewing of the original images along with their annotations, providing a comprehensive understanding of the context; (3) It displays spatial molecular features with optimized bandwidth, ensuring a smooth user experience; and (4) It bolsters data security by circumventing data transfers. AvailabilityScopeViewer is available at: https://datacommons.swmed.edu/scopeviewer ContactXiaowei.Zhan@UTSouthwestern.edu, Guanghua.Xiao@UTSouthwestern.edu Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2023

Quantification of glutathione with high throughput live-cell imaging

Reduction oxidation (redox) reactions are central in life and altered redox state is associated with a spectrum of human diseases. Glutathione (GSH) is the most abundant antioxidant in eukaryotic cells and plays critical roles in maintaining redox homeostasis. Thus, measuring intracellular GSH level is an important method to assess the redox state of organism. The currently available GSH probes are based on irreversible chemical reactions with glutathione and cant monitor the real-time glutathione dynamics. Our group developed the first reversible reaction based fluorescent probe for glutathione, which can measure glutathione levels at high resolution using a confocal microscope and in the bulk scale with a flow cytometry. Most importantly it can quantitatively monitor the real-time GSH dynamics in living cells. Using the 2nd generation of GSH probe, RealThiol (RT), this study measured the GSH level in living Hela cells after treatment with varying concentrations of DL-Buthionine sulfoximine (BSO) which inhibits GSH synthesis, using a high throughput imaging system, Cytation 5 cell imaging reader. The results revealed that GSH probe RT at the concentration of 2.0 {micro}M accurately monitored the BSO treatment effect on GSH level in the Hela cells. The present results demonstrated that the GSH probe RT is sensitive and precise in GSH measurement in living cells at a high throughput imaging platform and has the potential to be applied to any cell lines.

biochemistry↗

bioRxiv2023

Malaria resistance-related biological adaptation and complex evolutionary footprints of Tai-Kadai people inferred from 796 genomes

Pathogen-host adaptative interaction and complex population demographical processes, including admixture, drift and Darwen selection, have considerably shaped the Neolithic-to-Modern Western Eurasian population structure and genetic susceptibility to modern human diseases. However, the genetic footprints of evolutionary events in East Asia keep unknown as the underrepresentation of genomic diversity and the design of large-scale population studies. We reported one aggregated database of genome-wide-SNP variations from 796 Tai-Kadai (TK) genomes, including Bouyei first reported here, to explore the genetic history, population structure and biological adaptative features of TK-speaking people from Southern China and Southeast Asia. We found geography-related population substructure among TK-speaking people using the state-of-the-art population genetic structure reconstruction techniques based on the allele frequency spectrum and haplotype-resolved phased fragments. We found that the Northern TK-speaking people from Guizhou harboured one TK-dominant ancestry maximised in Bouyei people, and the Southern one from Thailand obtained more influences from Southeast Asians and indigenous people. We reconstructed the fitted admixture models and demographic graphs, which showed that TK-speaking people received gene flow from ancient rice farmer-related lineages related to the Hmong-Mien and Austroasiatic people and Northern millet farmers associated with the Sino-Tibetan people. Biological adaptation focused on our identified unique TK lineages related to Bouyei showed many adaptive signatures conferring Malaria resistance and low-rate lipid metabolism. Further gene enrichment, the allele frequency distribution of derived alleles, and their correlation with the incidence of Malaria further confirmed that CR1 played an essential role in the resistance of Malaria in the ancient "Baiyue" tribes.

genetics↗

bioRxiv2023

Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezualen Equine Encephalitis virus within olfactory sensory neurons

Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. Here, we utilized an established murine model of intranasal infection with VEEV to assess the cellular targets and IFN signaling responses after VEEV exposure. We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 hours during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFN triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFN treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFN for the treatment of human encephalitic alphavirus exposures. AUTHOR SUMMARYVenezuelan Equine Encephalitis virus (VEEV) may enter the brain through the nasal cavity upon intranasal exposure. The nasal cavity normally displays brisk antiviral immune responses, thus it is unclear why this type of exposure leads to fatal VEEV infection. Using an established murine model of intranasal infection with VEEV we identified the initial targets of infection within the nasal cavity and found that antiviral immune responses to virus at this site and during brain infection are delayed for up to 48 hours. Thus, administration of a single intranasal dose of recombinant IFN at the time of or early after infection improved early antiviral immune responses and suppressed viral replication, which delayed onset of brain infection and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the nasal cavity, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFN for the treatment of human VEEV exposures.

immunology↗

bioRxiv2023

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people inferred from 500 whole genome data from 39 populations

Tibeto-Burman (TB) people have tried to adapt to the hypoxic, cold and high-UV high-altitude Tibetan Plateau and complex disease exposure in the lowland wet and hot rainforest since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB people and their interaction mechanism remained unknown. We generated a whole-genome-based meta-database of 500 individuals from 39 TB populations from East Asia and Southeast Asia and presented a comprehensive landscape of genetic diversity, admixture history and differentiated adaptative features of geographically different TB people. We identified geography/language-related genetic differentiation among Tibetan Plateau, Tibetan-Yi-Corridor (TYC) and Southeast Asian TB people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between TYC people and ancient YR people supported the Northern origin hypothesis of TB people. We reported population substructure-related differentiated biological adaptative signatures between highland Tibetans and lowland TB people and between geographically different Lolo speakers. Highland adaptative EPAS1 and EGLN variants riched in Tibetans but lacked in TYC people whose adaptation is associated with the physical features and skin pigmentation (EDAR and SLC24A5), hepatic alcohol metabolism (ALDH9A1), regulation of cell-cell adhesion of muscle cells (CTNNA3) and immune/fat metabolism-related adaptative signature. TB-related genomic resources provided new insights into the genetic basis of phenotype differences and better reference for the anthropologically-informed sampling design in biomedical and genomic cohort research.

genetics↗

bioRxiv2023

Integrating Image and Molecular Profiles for Spatial Transcriptomics Analysis

The spatially resolved transcriptomics (SRT) field has revolutionized our ability to comprehensively leverage image and molecular profiles to elucidate spatial organization of cellular microenvironments. Current clustering analysis of SRT data primarily relies on molecular information and fails to fully exploit the morphological features present in histology images, leading to compromised accuracy and interpretability. To overcome these limitations, we have developed a multi-stage statistical method called iIMPACT. It includes a finite mixture model to identify and define histology-based spatial domains based on AI-reconstructed histology images and spatial context of gene expression measurements, and a negative binomial regression model to detect domain-specific spatially variable genes. Through multiple case studies, we demonstrate iIMPACT outperformed existing methods, confirmed by ground truth biological knowledge. These findings underscore the accuracy and interpretability of iIMPACT as a new clustering approach, providing valuable insights into the cellular spatial organization and landscape of functional genes within spatial transcriptomics data.

bioinformatics↗

bioRxiv2023

Deciphering Phage-Host Specificity Based on the Association of Phage Depolymerases and Bacterial Surface Glycan with Deep Learning

Phage tailspike proteins are depolymerases that target diverse bacterial surface glycans with high specificity, determining the host-specificity of numerous phages. To address the challenge of identifying tailspike proteins due to their sequence diversity, we developed SpikeHunter, an approach based on the ESM-2 protein language model. Using SpikeHunter, we successfully identified 231,965 tailspike proteins from a dataset comprising 8,434,494 prophages found within 165,365 genomes of five common pathogens. Among these proteins, 143,035 tailspike proteins displayed strong associations with serotypes. Moreover, we observed highly similar tailspike proteins in species that share closely related serotypes. We found extensive domain swapping in all five species, with the C-terminal domain being significantly associated with host serotype highlighting its role in host range determination. Our study presents a comprehensive cross-species analysis of tailspike protein to serotype associations, providing insights applicable to phage therapy and biotechnology.

bioinformatics↗

bioRxiv2023

Expansion-assisted selective plane illumination microscopy for nanoscale imaging ofcentimeter-scale tissues

Recent advances in tissue processing, labeling, and fluorescence microscopy are providing unprecedented views of the structure of cells and tissues at sub-diffraction resolutions and near single molecule sensitivity, driving discoveries in diverse fields of biology, including neuroscience. Biological tissue is organized over scales of nanometers to centimeters. Harnessing molecular imaging across intact, three-dimensional samples on this scale requires new types of microscopes with larger fields of view and working distance, as well as higher throughput. We present a new expansion-assisted selective plane illumination microscope (ExA-SPIM) with aberration-free 1.5 {micro}mx1.5 {micro}mx3 {micro}m optical resolution over a large field of view (10.6x8.0 mm2) and working distance (35 mm) at speeds up to 946 megavoxels/sec. Combined with new tissue clearing and expansion methods, the microscope allows imaging centimeter-scale samples with 375 nm lateral and 750 nm axial resolution (4x expansion), including entire mouse brains, with high contrast and without sectioning. We illustrate ExA-SPIM by reconstructing individual neurons across the mouse brain, imaging cortico-spinal neurons in the macaque motor cortex, and visualizing axons in human white matter.

neuroscience↗

bioRxiv2023

Functionally and metabolically divergent melanoma-associated macrophages originate from common bone-marrow precursors

Melanomas display high numbers of tumor-associated macrophages (TAMs), which correlate with worse prognosis. Harnessing macrophages for therapeutic purposes has been particularly challenging due to their heterogeneity, based on their ontogeny and function and driven by the tissue-specific niche. In the present study, we used the YUMM1.7 model to better understand melanoma TAM origin and dynamics during tumor progression, with potential therapeutic implications. We identified distinct TAM subsets based on F4/80 expression, with the F4/80high fraction increasing over time and displaying tissue-resident-like phenotype. While skin-resident macrophages showed mixed on-togeny, F4/80+ TAM subsets in i.d. YUMM1.7 tumors originated almost exclusively from bone-marrow precursors. Mul-tiparametric analysis of macrophage phenotype showed a temporal divergence of F4/80+ TAM subpopulations, which also differed from skin-resident subsets, and from their monocytic precursors. Overall, F4/80+ TAMs displayed co-ex-pression of M1- and M2-like canonical markers, while RNA-seq and pathway analysis showed differential immunosup-pressive and metabolic profiles. GSEA showed F4/80high TAMs to rely on oxidative phosphorylation, with increased proliferation and protein secretion while F4/80low cells had high pro-inflammatory and intracellular signaling pathways, with lipid and polyamine metabolism. Overall, the present in-depth characterization provides further evidence of the ontogeny of the evolving melanoma TAMs, whose gene expression profiles matched recently-identified TAM clusters in other tumor models and human cancers. These findings provide evidence for potentially targeting specific immunosup-pressive TAMs in advanced tumor stages.

immunology↗

bioRxiv2023

IPEV: Identification of Prokaryotic and Ekaryotic Vrus-derived sequences in virome using deep learning

BackgroundThe virome obtained through virus-like particle enrichment contain a mixture of prokaryotic and eukaryotic virus-derived fragments. Accurate identification and classification of these elements are crucial for understanding their roles and functions in microbial communities. However, the rapid mutation rates of viral genomes pose challenges in developing high-performance tools for classification, potentially limiting downstream analyses. FindingsWe present IPEV, a novel method that combines trinucleotide pair relative distance and frequency with a 2D convolutional neural network for distinguishing prokaryotic and eukaryotic viruses in viromes. Cross-validation assessments of IPEV demonstrate its state-of-the-art precision, significantly improving the F1-score by approximately 22% on an independent test set compared to existing methods when query viruses share less than 30% sequence similarity with known viruses. Furthermore, IPEV outperforms other methods in terms of accuracy on most real virome samples when using sequence alignments as annotations. Notably, IPEV reduces runtime by 50 times compared to existing methods under the same computing configuration. We utilized IPEV to reanalyze longitudinal samples and found that the gut virome exhibits a higher degree of temporal stability than previously observed in persistent personal viromes, providing novel insights into the resilience of the gut virome in individuals. ConclusionsIPEV is a high-performance, user-friendly tool that assists biologists in identifying and classifying prokaryotic and eukaryotic viruses within viromes. The tool is available at https://github.com/basehc/IPEV.

bioinformatics↗

bioRxiv2023

Genomic and transcriptomic analysis revealed new insights into the influence of key T6SS genes hcp and vgrG on drug resistance and interbacterial competition in Klebsiella pneumoniae

Type VI secretion systems (T6SSs) act as a molecular weapon in interbacterial competition and play an important role in cell-cell interactions. Different species of bacteria use their T6SSs to perform a variety of functions according to ecological niche. Therefore, it is necessary to better understand the T6SS potential of Klebsiella pneumoniae (K. pneumoniae), a common clinical opportunistic pathogen. Here, we conducted a genomic analysis on the evolution, T6SS, virulence and antimicrobial resistance of 65 K. pneumoniae in patients with different infections. And we combined transcriptome analysis after knockout of key gene in T6SS of this species. Results showed that genes encoding a T6SS were present in all K. pneumoniae in this study, and there was no correlation was found between T6SS cluster and carbapenem resistance and virulence genes. Differentially expressed genes (DEGs) including 1298 co-upregulated and 1714 co-downregulated were identified after hcp or vgrG deletion. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis have demonstrated common changes in quorum sensing, propionate metabolism and other pathways. And we found that the deletion of hcp or vgrG genes up-regulated of beta-lactam (blaKPC-2) and other resistance genes. Interbacterial competition experiments showed that hcp and vgrG are essential genes for competitive ability of ST11 K. pneumoniae. Taken together, the entire study provides further insight into the investigation of T6SS in K. pneumoniae through genomic and transcriptomic analysis. ImportanceGram-negative bacteria use T6SS to deliver toxin effectors to interact with neighboring cells for niche advantage. K. pneumoniae is an opportunistic nosocomial pathogen that often carriers multiple cope T6SSs, but the function of its T6SS has not yet elucidated. Here, we performed a genomic analysis of 65 clinical K. pneumoniae strains, in order to explore the relationship between T6SS and virulence and resistance genes. We also study the repertoire after knockout of key gene in T6SS of this species by transcriptomics. It was suggested that T6SS is associated with drug resistance, and its key genes hcp and vgrG are critical for the interspecies competition of K. pneumoniae.

microbiology↗

bioRxiv2023

Comprehensively defining cellular specializations for initiating parallel auditory pathways in the mouse cochlear nucleus

The cochlear nuclear complex (CN), the starting point for all central auditory processing, comprises a suite of neuronal cell types that are highly specialized for neural coding of acoustic signals, yet molecular logic governing cellular specializations remains unknown. By combining single-nucleus RNA sequencing and Patch-seq analysis, we reveal a set of transcriptionally distinct cell populations encompassing all previously observed types and discover multiple new subtypes with anatomical and physiological identity. The resulting comprehensive cell-type taxonomy reconciles anatomical position, morphological, physiological, and molecular criteria, enabling the determination of the molecular basis of the remarkable cellular phenotypes in the CN. In particular, CN cell-type identity is encoded in a transcriptional architecture that orchestrates functionally congruent expression across a small set of gene families to customize projection patterns, input-output synaptic communication, and biophysical features required for encoding distinct aspects of acoustic signals. This high-resolution account of cellular heterogeneity from the molecular to the circuit level illustrates molecular logic for cellular specializations and enables genetic dissection of auditory processing and hearing disorders with unprecedented specificity.

neuroscience↗

bioRxiv2023

An Interpretable Bayesian Clustering Approach with Feature Selection for Analyzing Spatially Resolved Transcriptomics Data

SO_SCPLOWUMMARYC_SCPLOWRecent breakthroughs in spatially resolved transcriptomics (SRT) technologies have enabled comprehensive molecular characterization at the spot or cellular level while preserving spatial information. Cells are the fundamental building blocks of tissues, organized into distinct yet connected components. Although many non-spatial and spatial clustering approaches have been used to partition the entire region into mutually exclusive spatial domains based on the SRT high-dimensional molecular profile, most require an ad-hoc selection of less interpretable dimensional-reduction techniques. To overcome this challenge, we propose a zero-inflated negative binomial mixture model to cluster spots or cells based on their molecular profiles. To increase interpretability, we employ a feature selection mechanism to provide a low-dimensional summary of the SRT molecular profile in terms of discriminating genes that shed light on the clustering result. We further incorporate the SRT geospatial profile via a Markov random field prior. We demonstrate how this joint modeling strategy improves clustering accuracy, compared with alternative state-of-the-art approaches, through simulation studies and two real data applications.

bioinformatics↗

bioRxiv2023

Ex-Lactobacillus Strains with Intrinsic Propensity to Stabilize Pickering Oil-in-Water Emulsions

Knowledge of surface characteristics is a major step in the evaluation of bacterial cells for potential use as Pickering emulsion stabilizers. Here, the cell surface characteristics of 31 strains of the ex-Lactobacillus genus were studied with the aim of evaluating their intrinsic abilities to serve as Pickering stabilizers of oil-in-water emulsions. About 77.42% of the tested strains demonstrated relatively highly negative zeta potential (-43.76 mV [≤] zeta potential [≤] -19.23 mV), while [~]58% of the strains demonstrated high cell surface hydrophobicity (microbial adhesion to hexadecane or MATH [≥] 30%). By combining these findings, four different cell surface features were defined (I, II, II and IV). Strains mainly demonstrated the type I surface feature ([~]45%), with most expressing strongly negative zeta potential and high surface hydrophobicity (zeta potential < -15 mV and MATH [≥] 30%, respectively). It appeared that the abundance of negative charge on the surfaces of ex-Lactobacillus cells positively influences surface hydrophobicity. Assessment of intrinsic Pickering stabilization potential using 12 selected strains indicated that four strains showed profound droplet size stability. At least one strain was observed to have natural propensity to form relativley compact and small emulsion droplets (63{+/-}3 {micro}m), leading to enhanced firmness and storage stability of the Pickering emulsions.

microbiology↗

bioRxiv2023

Directed-evolution mutations of adenine base editor ABE8e improve its DNA-binding affinity and protein stability

Adenine base editors (ABEs), consisting of CRISPR-associated (Cas) nickase and deaminase, can convert the A:T base pair to G:C. Previous studies have shown that ABE8e, a directed-evolution variant of ABE7.10 with eight amino-acid mutations in its deaminase TadA-8e, has higher base editing activity than ABE7.10. However, it remains unclear how the directed-evolution mutations of ABE8e increase its editing activity. Here, we combined molecular dynamics (MD) simulations and experimental measurements to elucidate the molecular origin of the activity enhancement by these mutations. MD simulations and microscale thermophoresis measurements showed that TadA-8e has a higher DNA-binding affinity than TadA-7.10, and the main driving force is electrostatic interactions. The directed-evolution mutations increase the positive charge density in the DNA-binding region, thereby enhancing the electrostatic attractions with DNA. We showed that R111 is the key mutation for the enhanced binding to DNA, which explains why the ABE-8e activity was dramatically reduced when R111 was mutated back to the original T. Unexpectedly, we also found that these mutations improve the thermal stability of TadA-8e by [~]12{degrees}C (Tm). Our results indicate that the editing activities of ABEs are closely related to their DNA-binding affinity and protein stability, thus providing a rational basis for their optimization. Author SummaryAdenine-to-guanine mutations account for 47% of known disease-causing point mutations in humans. Adenine base editors (ABEs), which can restore the guanine mutation to adenine, are a promising tool for precision gene therapy. ABE8e is the most widely used editor today due to its high editing efficacy and was derived from the first-generation base editor ABE7.10 by directed evolution. Compared to ABE7.10, ABE8e contains 8 directed-evolution amino-acid mutations. Understanding how these mutations affect the efficiency of ABE8e is important for the development of efficient base editors. In this study, we combined computational and experimental approaches to investigate how these mutations affect the editing activity of ABE8e. Our results showed that these directed-evolution mutations improve the DNA binding affinity and the protein stability of ABE8e, by enhancing electrostatic and hydrogen bonding interactions. Therefore, our study provides valuable insights for the design of more efficient base editors.

molecular biology↗

bioRxiv2023

Toxic anti-phage defense proteins inhibited by intragenic antitoxin proteins

Recombination-promoting nuclease (Rpn) proteins are broadly distributed across bacterial phyla, yet their functions remain unclear. Here we report these proteins are new toxin-antitoxin systems, comprised of genes-within-genes, that combat phage infection. We show the small, highly variable Rpn C-terminal domains (RpnS), which are translated separately from the full-length proteins (RpnL), directly block the activities of the toxic full-length proteins. The crystal structure of RpnAS revealed a dimerization interface encompassing a helix that can have four amino acid repeats whose number varies widely among strains of the same species. Consistent with strong selection for the variation, we document plasmid-encoded RpnP2L protects Escherichia coli against certain phages. We propose many more intragenic-encoded proteins that serve regulatory roles remain to be discovered in all organisms. SignificanceHere we document the function of small genes-within-genes, showing they encode antitoxin proteins that block the functions of the toxic DNA endonuclease proteins encoded by the longer rpn genes. Intriguingly, a sequence present in both long and short protein shows extensive variation in the number of four amino acid repeats. Consistent with a strong selection for the variation, we provide evidence that the Rpn proteins represent a phage defense system.

microbiology↗

bioRxiv2023

Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis

Besides its mitochondria-based anti-apoptotic role, Bcl-xL also travels to the nucleus to promote cancer metastasis by upregulating global histone H3 trimethyl Lys4 (H3K4me3) and TGF{beta} transcription. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates H3K4me3 modification are not understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced cell migration and metastasis in mouse models. Furthermore, knockout of CtBP2 suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGF{beta} mRNA upregulation as well as cell invasion. Moreover, cleavage under targets and release using nuclease (CUT&RUN) coupled with next generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor region of genes encoding TGF{beta} and its signaling pathway in the cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1.

cancer biology↗

bioRxiv2023

Evidence for Involvement of WDPCP Gene in Alcohol Consumption, Lipid Metabolism, and Liver Cirrhosis

Alcohol consumption continues to cause a significant health burden globally. The advent of genome-wide association studies has unraveled many genetic loci associated with alcohol consumption. However, the biological effect of these loci and the pathways involved in alcohol consumption and its health consequences such as alcohol liver disease (ALD) remain to be elucidated. We combined human studies with model organisms Drosophila melanogaster and Caenorhabditis elegans to shed light on the molecular mechanisms underlying alcohol consumption and the health outcomes caused by alcohol intake. Using genetics and metabolite data within the Airwave study, a sample of police forces in the UK, we performed several analyses to identify changes in circulating metabolites that are triggered by alcohol consumption. We selected a set of genes annotated to genetic variants that are (1) known to be implicated in alcohol consumption, (2) are linked to liver function, and (3) are associated with expression (cis-eQTL) of their annotated genes. We used mutations and/or RNA interference (RNAi) to suppress the expression of these genes in C. elegans and Drosophila. We examined the effect of this suppression on ethanol consumption and on the sedative effects of ethanol. We also investigated the alcohol-induced changes in triacylglycerol (TGA) levels in Drosophila and tested differences in locomotion of C. elegans after acute exposure to ethanol. In human population, we found an enrichment of the alcohol-associated metabolites within the linoleic acid (LNA) and alpha linolenic acid (ALA) metabolism pathway. We further showed the effect of ACTR1B and MAPT on locomotion in C. elegans after exposure to ethanol. We demonstrated that three genes namely WDPCP, TENM2 and GPN1 modify TAG levels in Drosophila. Finally, we showed that gene expression of WDPCP in human population is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on metabolism of lipids and pinpoints WDPCP as a gene with potential impact on fat accumulation upon exposure to ethanol suggesting a possible pathway to ALD.

genetics↗