Biology subjects

Meng, Y.

Publications and source records attributed to Meng, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Rtf1 HMD domain facilitates global histone H2B monoubiquitination and regulates morphogenesis and virulence in the meningitis-causing pathogen Cryptococcus neoformans

Rtf1 is generally considered to be a subunit of the Paf1 complex (Paf1C), which is a multifunctional protein complex involved in histone modification and RNA biosynthesis at multiple stages. Rtf1 is stably associated with the Paf1C in Saccharomyces cerevisiae, but not in other species including humans. Little is known about its function in human fungal pathogens. Here, we show that Rtf1 is required for facilitating H2B monoubiquitination (H2Bub1), and regulates fungal morphogenesis and pathogenicity in the meningitis-causing fungal pathogen Cryptococcus neoformans. Rtf1 is not tightly associated with the Paf1C, and its histone modification domain (HMD) is sufficient to promote H2Bub1 and the expression of genes related to fungal mating and filamentation. Moreover, Rtf1 HMD fully restores fungal morphogenesis and pathogenicity; however, it fails to restore defects of thermal tolerance and melanin production in the rtf1{Delta} strain background. The present study establishes a role for cryptococcal Rtf1 as a Paf1C-independent regulator in regulating fungal morphogenesis and pathogenicity, and highlights the function of HMD in facilitating global H2Bub1 in C. neoformans.

molecular biology↗

bioRxiv2024

The dual resistance mechanism of CYP325G4 and CYP6AA9 in Culex pipiens pallens legs according to transcriptome and proteome analysis

Mosquitoes within the Culex pipiens complex play a crucial role in human disease transmission. Insecticides, especially pyrethroids, are used to control these vectors. Mosquito legs are the main entry point and barrier for insecticides to gain their neuronal targets. However, the resistance mechanism in mosquito legs is unclear. Herein, we employed transcriptomic analyses and isobaric tags for relative and absolute quantitation techniques to investigate the resistance mechanism, focusing on Cx. pipiens legs. We discovered 2346 differentially expressed genes (DEGs) between deltamethrin-resistant (DR) and deltamethrin-sensitive (DS) mosquito legs, including 41 cytochrome P450 genes. In the same comparison, we identified 228 differentially expressed proteins (DEPs), including six cytochrome P450 proteins). Combined transcriptome and proteome analysis revealed only two upregulated P450 genes, CYP325G4 and CYP6AA9. The main clusters of DEGs and DEPs were associated with metabolic processes, such as cytochrome P450-mediated metabolism of drugs and xenobiotics. Transcription analysis revealed high CYP325G4 and CYP6AA9 expression in the DR strain at 72 hours post-eclosion compared with that in the DS strain, particularly in the legs. Mosquitoes knocked down for CYP325G4 were more sensitive to deltamethrin than the controls. CYP325G4 knockdown reduced the expression of several chlorinated hydrocarbon (CHC)-related genes, which altered the cuticle thickness and structure. Conversely, CYP6AA9 knockdown increased CHC gene expression without altering cuticle thickness and structure. P450 activity analysis demonstrated that CYP325G4 and CYP6AA9 contributed to metabolic resistance in the midgut and legs. This study identified CYP325G4 as a novel mosquito deltamethrin resistance factor, being involved in both metabolic and cuticular resistance mechanisms. The previously identified CYP6AA9 was investigated for its involvement in metabolic resistance and potential cuticular resistance in mosquito legs. These findings enhance our comprehension of resistance mechanisms, identifying P450s as promising targets for the future management of mosquito vector resistance, and laying a theoretical groundwork for mosquito resistance management. Author SummaryCulex pipiens mosquitoes are the primary vector of the filamentous nematode, Wuchereria bancrofti and also involved in the transmission of other pathogens, such as West Nile virus (WNV), avian malarias, and avian pox virus. Insecticides, particularly pyrethroids, continue to be the primary method to control these significant vectors. Worryingly, resistance to insecticides has become widespread and is rapidly intensifying in Culex mosquitoes throughout China, posing a threat to the efficacy of insecticides. Legs are the main sites of contact with ITNs and sprayed insecticides, and the insecticides have to penetrate the leg cuticle to reach their targets.Therefore, the resistance mechanisms in mosquito legs deserve further investigation. Several reports have found a certain amount of P450 in insect legs. Unfortunately, none of the above reports have conducted further functional studies on P450s in the legs. Here, we have identified two P450 enzymes, CYP325G4 and CYP6AA9, through the integrated analysis of transcriptomics and proteomics. CYP325G4 enriched in the cuticle of resistant mosquitoes might possess a dual resistance mechanism involving metabolic resistance and cuticle resistance. CYP6AA9 was slightly different, possibly exerting metabolic resistance as its main function and also being involved in cuticle synthesis. Understanding the dual resistance mechanism of P450s in the metabolism of pyrethroid insecticides will have an important role in optimizing vector control strategies.

physiology↗

bioRxiv2024

Impact of genomic background and developmental state on signaling pathways and response to therapy in Glioblastoma patient-derived cells

Glioblastoma (GBM) tumors represents diverse genomic epigenomic, and transcriptional landscapes, with significant intratumoral heterogeneity that challenges standard of care treatments involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed targeted proteomics to assess the response of a genomically-diverse panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation, growth factor withdrawal and traditional high fetal bovine serum culture. Our findings revealed a complex crosstalk and co-activation of key oncogenic signaling in CSCs and diverse patterns of response to these external stimuli. Using RNA sequencing and DNA methylation, we observed common adaptations in response to astrocytic differentiation of CSCs across genomically distinct models, including BMP-Smad pathway activation, reduced cholesterol biosynthesis, and upregulation of extracellular matrix components. Notably, we observed that these differentiated CSC progenies retained a subset of stemness genes and the activation of cell survival pathways. We also examined the impact of differentiation state and genomic background on GBM cell sensitivity and transcriptional response to TMZ and RT. Differentiation of CSCs increased resistance to TMZ but not to RT. While transcriptional responses to these treatments were predominantly regulated by p53 in wild-type p53 GBM cells, its transcriptional activity was modulated by the differentiation status and treatment modality. Both mutant and wild-type p53 models exhibited significant activation of a DNA-damage associated interferon response in CSCs and differentiated cells, suggesting this pathway may play a wider role in GBM response to TMZ and RT. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.

cancer biology↗

bioRxiv2024

ATG6 interacting with NPR1 increases Arabidopsis thaliana resistance to Pst DC3000/avrRps4 by increasing its nuclear accumulation and stability

Autophagy-related gene 6 (ATG6) plays a crucial role in plant immunity. Nonexpressor of pathogenesis-related genes1 (NPR1) acts as a signaling hub of plant immunity. However, the relationship between ATG6 and NPR1 is unclear. Here, we find that ATG6 directly interacts with NPR1. ATG6 overexpression significantly increased nuclear accumulation of NPR1. Furthermore, we demonstrate that ATG6 increases NPR1 protein levels and improves its stability. Interestingly, ATG6 promotes the formation of SINCs (SA-induced NPR1 condensates)-like condensates. Additionally, ATG6 and NPR1 synergistically promote the expression of pathogenesis-related genes. Further results showed that silencing ATG6 in NPR1-GFP exacerbates Pst DC3000/avrRps4 infection, while double overexpression of ATG6 and NPR1 synergistically inhibits Pst DC3000/avrRps4 infection. In summary, our findings unveil an interplay of NPR1 with ATG6 and elucidate important molecular mechanisms for enhancing plant immunity. HighlightWe unveil a novel relationship in which ATG6 positively regulates NPR1 in plant immunity.

plant biology↗

bioRxiv2023

Phylogeny-metabolism dual-directed single-cell genomics for dissecting and mining ecosystem function

Although microbiome-wide association studies (MWAS) have uncovered many marker organisms for an ecosystem trait, mechanisms of most microbiota-mediated processes remain elusive, due to challenges in validating the markers in situ metabolic activities and tracing such activities to individual genomes. Here we introduced a phylogeny-metabolism dual-directed single-cell genomics approach called Fluorescence-In-Situ-Hybridization-guided Single-Cell Raman-activated Sorting and Sequencing (FISH-scRACS-Seq). It directly localizes individual cells from target taxon via a FISH probe for marker organism, profiles their in situ metabolic functions via single-cell Raman spectra, sorts cells of target taxonomy and target metabolism, and produces indexed, high-coverage and precisely-one-cell genomes. From cyclohexane-contaminated seawater, cells representing the MWAS-derived marker taxon of {gamma}-Proteobacteria and that are actively degrading cyclohexane in situ were directly identified via FISH and Raman respectively, then sorted and sequenced for one-cell full genomes. In such a Pseudoalteromonas fuliginea cell, we discovered a three-component cytochrome P450 system that can convert cyclohexane to cyclohexanol in vitro, representing a previously unknown group of cyclohexane-degrading enzymes and organisms. By culture-independently unveiling enzymes, pathways, genomes and their in situ functions specifically for those single-cells with ecological relevance, FISH-scRACS-Seq is a rational and generally applicable approach for dissecting and mining microbiota functions. TeaserFISH-scRACS-Seq is a new strategy to dissect microbiota functional mechanism at single-cell resolution.

microbiology↗

bioRxiv2023

Viscoelastic Deformability Cytometry: Ultra-high Throughput Platform for Mechanical Phenotyping of Cells in Liquid and Solid Biopsies

Due to the differences in mechanical properties between cancer cells and their benign counterparts, the mechanical characteristics of cells have emerged as a significant feature in diagnosing cancer. Consequently, measuring cell deformability as a means of mechanical phenotyping is promising for both the detection and classification of the disease. However, performing high-throughput single-cell deformability measurements on liquid or solid tissue biopsies remains a significant challenge within a clinical setting. Herein, we introduce an ultra-high throughput viscoelastic-based microfluidic platform to measure the cell mechanical properties at rates of up to 100,000 cells/s. Thanks to the viscoelastic property of the fluid, cells are focused and deformed within the same platform obviating the need for any sheath fluid. We used the presented platform for cell phenotyping in both liquid and solid tumor biopsies, such as identification of malignant lymphocytes in peripheral blood samples and glioblastoma-type cell classification from solid tumor samples. The presented platform has the potential to open new opportunities in the assessment of cancer, enable precise mechanical profiling of rare cells, and facilitate sensitive diagnostic applications.

bioengineering↗

bioRxiv2023

Impossible ecologies: Interaction networks and stability of coexistence in ecological communities

Does an ecological community allow stable coexistence? Identifying the general principles that determine the answer to this question is a central problem of theoretical ecology. Random matrix theory approaches have uncovered the general trends of the effect of competitive, mutualistic, and predator-prey interactions between species on stability of coexistence. However, an ecological community is determined not only by the counts of these different interaction types, but also by their network arrangement. This cannot be accounted for in a direct statistical description that would enable random matrix theory approaches. Here, we therefore develop a different approach, of exhaustive analysis of small ecological communities, to show that this arrangement of interactions can influence stability of coexistence more than these general trends. We analyse all interaction networks of N [<=] 5 species with Lotka-Volterra dynamics by combining exact results for N [<=] 3 species and numerical exploration. Surprisingly, we find that a very small subset of these networks are "impossible ecologies", in which stable coexistence is non-trivially impossible. We prove that the possibility of stable coexistence in general ecologies is determined by similarly rare "irreducible ecologies". By random sampling of interaction strengths, we then show that the probability of stable coexistence varies over many orders of magnitude even in ecologies that differ only in the network arrangement of identical ecological interactions. Finally, we demonstrate that our approach can reveal the effect of evolutionary or environmental perturbations of the interaction network. Overall, this work reveals the importance of the full structure of the network of interactions for stability of coexistence in ecological communities.

ecology↗

bioRxiv2023

OBIA: An Open Biomedical Imaging Archive

With the development of artificial intelligence (AI) technologies, biomedical imaging data play an important role in scientific research and clinical application, but the available resources are limited. Here we present Open Biomedical Imaging Archive (OBIA), a repository for archiving biomedical imaging and related clinical data. OBIA adopts five data objects (Collection, Individual, Study, Series, and Image) for data organization, accepts the submission of biomedical images of multiple modalities, organs, and diseases. In order to protect personal privacy, OBIA has formulated a unified de-identification and quality control process. In addition, OBIA provides friendly and intuitive web interface for data submission, browsing and retrieval, as well as image retrieval. As of September 2023, OBIA has housed data for a total of 937 individuals, 4136 studies, 24,701 series, and 1,938,309 images covering 9 modalities and 30 anatomical sites. Collectively, OBIA provides a reliable platform for biomedical imaging data management and offers free open access to all publicly available data to support research activities throughout the world. OBIA can be accessed at https://ngdc.cncb.ac.cn/obia.

bioinformatics↗

bioRxiv2023

A pro-inflammatory stem cell niche drives myelofibrosis through a targetable galectin 1 axis

Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. The majority of patients present with early-stage disease, but a substantial proportion progress to myelofibrosis and/or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and we lack therapies that reliably prevent or reverse fibrosis development. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the crosstalk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a quartet of immune and stromal cell lineages - with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells and pro-inflammatory fibroblasts. We identified the y-galactoside binding protein galectin 1 as a striking biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts, and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival following galectin 1 inhibition. In human bone marrow organoids, TNF increased galectin 1 expression, suggesting a feedback loop wherein the pro-inflammatory MPN clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a valuable resource for studying hematopoietic cell-niche interactions, with broad relevance for cancer-associated inflammation and disorders of tissue fibrosis.

cancer biology↗

bioRxiv2023

Using UAV-based temporal spectral indices to dissect changes in the stay green trait in wheat

Stay green (SG) in wheat, a beneficial trait for increasing yield and stress resistance, needs to be supported by analysis of the underlying genetic basis. Spectral reflectance indices (SIs) provide non-destructive tools to evaluate crop temporal senescence. However, few SI-based SG quantification pipelines for analyzing diverse wheat panels in the field are available. Here, we first applied SIs to monitor the senescence dynamics of 565 diverse wheat accessions from anthesis to maturation stages during two field seasons. Based on over 12,000 SIs data set, four SIs (NDVI, GNDVI, NDRE and OSAVI) were selected to develop relative stay green scores (RSGS) and the senescence of wheat populations occurs mainly at four developmental stages stage 1 (S1) to S4, accounting for the final SG indicators. A RSGS-based genome-wide association study identified 47 high-confidence quantitative trait loci (QTL) harboring 3,079 SNPs significantly associated with RSGS and 1,085 corresponding candidate genes in the two seasons; 15 QTL overlapped or were adjacent to known SG-related QTL or genes and the remaining QTL were novel. Finally, we selected three superior candidate genes (TraesCS6B03G0356400, TraesCS2B03G1299500, and TraesCS2A03G1081100) as examples by transcriptomes, gene annotation, and gene-based association analysis for further analysis and found that utilization of superior SG-related variation in China gradually increased following the Green Revolution. The study provides a useful reference for further SG-related gene discovery of favorable variations in diverse wheat panels.

genetics↗

bioRxiv2023

Ground-state pluripotent stem cells are characterized by Rac1-dependent Cadherin-enriched F-actin protrusions

Pluripotent Stem Cells (PSCs) exhibit extraordinary differentiation potentials that can be propagated in vitro and thus are commonly utilized in regenerative medicine. While different types of PSCs exist which correspond to different stages of pluripotency during embryogenesis, important aspects of their biology in terms of their cellular architecture and mechanobiology have been less well understood, thereby limiting their tissue engineering application potentials. Since the actin cytoskeleton is a primary determinant of cell mechanical properties, here we sought to investigate how the actin cytoskeleton may be differentially regulated in different states of pluripotency. Comparing ground-state naive mESCs and the corresponding converted prime epiblast stem cells (EpiSCs), we observed the actin cytoskeleton is drastically reorganized during the naive to prime pluripotency transition. Strikingly, we reported a distinctive actin organization that appears to be unique to the ground state mESCs, whereby the isotropic cortical networks are decorated with prominent actin-enriched structures which contain cadherin-based cell-cell junctional components, despite not locating at cell-cell junctions. We termed these structures "cadheropodia" and showed they arise from the cis-association of E-cadherin extracellular domain. Our measurements revealed that cadheropodia is under low mechanical tension and exhibits minimal calcium dependence, consistent with its putative dependence on cis-interaction. Further, we identified Rac1 as a negative regulator of cadheropodia whereby active Rac1 induces its fragmentation and dissociation of {beta}-catenin. Taken together, we described a novel actin-based structures in the ground-state mESCs, which may have potential roles in ground-state pluripotency and serve as useful structural markers to distinguish heterogeneous population of pluripotent stem cells.

cell biology↗

bioRxiv2023

A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes

Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A lead example is the >150 Amaryllidaceae alkaloids (AmAs) including galantamine, an FDA-approved treatment for Alzheimers disease. We show that while AmAs accumulate to high levels in many tissues in daffodils, biosynthesis is localized to nascent, growing tissue at the base of leaves. A similar trend is found for the production of steroidal alkaloids (e.g. cyclopamine) in corn lily. This model of active biosynthesis enabled elucidation of a complete set of biosynthetic genes for the production of AmAs. Taken together, our work sheds light on the developmental and enzymatic logic of diverse alkaloid biosynthesis in daffodil. More broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes where plants are protected from herbivory through active charging of newly formed cells with eukaryotic toxins that persist as aboveground tissue develops.

biochemistry↗

bioRxiv2023

Progressive Senescence Programs Induce Intrinsic Vulnerability to Aging-related Breast Cancer

Cancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we built a chronological molecular clock at the single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in mice. We found that the mammary aging process was asynchronous and progressive, initiated by an early senescence program with elevated NF-kB and P53 signaling, succeeded by an entropic late senescence program with reduced NF-kB and P53 signaling and enhanced PI3K-Akt-mTOR, Wnt, Notch and pluripotent activity, vulnerable to cancer predisposition. The transition towards senescence program was governed by the master stem cell factor Bcl11b, loss of which accelerated mammary ageing with enhanced DMBA-induced tumor formation. We identified a drug TPCA-1 that can elevate Bcl11b, rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings established a molecular portrait of progressive mammary cell aging and elucidated the transcriptional regulatory network bridging mammary aging and cancer predisposition, which can be modulated to control cancer initiation; therefore, this study has potential implications for the management of cancer prevalence in the aged.

cancer biology↗

bioRxiv2023

Integrated multi-omics data reveals the molecular subtypes and the contruction of novel signature to aid Immunotherapy

Malignant cancer exhibits a severe imbalance between the active of immune response and tolerance. And the different and connection between the establishment and deficiency of the tumor immune response is still unknown entirely. Here, we used ten clustering algorithms based on five immune cells infiltration matrix to identified two specific molecular subtypes and determine its potential clinical outcomes and immune response effect. The cluster A subtype can be called the cold inflammatory subtype, which revealed the worst prognosis. And the cluster B can be identified as hot inflammatory subtype with high activated immune-related pathways. Then we used the WGCNA algorithms and limma to confirm the driven genes between the cluster A and B. 67 genes were identified the cluster A signature genes, and based on that we used the ssgsea algorithm to quantize the two subtypes. We confirmed the high score group had high activated level of immune activity pathways and better survival rate. The tumorigenesis-associated pathways were analysed in low score group, indicating active cell proliferation may be associated with poor prognosis. An in-silico drug screen predicted the erlotinib can be an effective compound in low score group based on the lung cancer cell line. Our research confirmed that the score can worked as an effective immunotherapy index, which provide a promising therapeutic strategies on immune therapeutics for lung adenocarcinoma.

cancer biology↗

bioRxiv2023

Genomic determinants of soil depth niche partitioning in Gagatemarchaeaceae, a novel family of deeply-rooted Thaumarchaeota

Knowledge of deeply-rooted non-ammonia oxidising Thaumarchaeota lineages from terrestrial environments is scarce, despite their abundance in acidic soils. Here, 15 new deeply-rooted thaumarchaeotal genomes were assembled from acidic topsoils (0-15cm) and subsoils (30-60 cm), most of them corresponding to two genera of terrestrially prevalent Gagatemarchaeaceae (previously known as thaumarchaeotal Group I.1c). Unlike previous predictions, metabolic annotations suggest Gagatemarchaeaceae perform aerobic respiration and use various organic carbon sources. Evolutionary speciation between topsoil and subsoil lineages happened early in Gagatemarchaeaceae history, with significant metabolic and genomic trait differences. Reconstruction of the evolutionary mechanisms showed that the genome expansion in topsoil Gagatemarchaeaceae resulted from extensive early lateral gene acquisition, followed by progressive gene duplication throughout evolutionary history. Ancestral trait reconstruction using the expanded genomic diversity also refuted the previous hypothesis of a Thaumarchaeota thermophilic ancestor. Ultimately, this study provides an attractive model for studying mechanisms driving niche partitioning between spatially related ecosystems.

microbiology↗

bioRxiv2023

Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.

cell biology↗

bioRxiv2022

Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans

Cryptococcus neoformans poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for multidrug resistance in C. neoformans. Cells with the disrupted ISW1 gene exhibited profound resistance to multiple antifungal drugs. Mass spectrometry analysis revealed that Isw1 is both acetylated and ubiquitinated, suggesting that an interplay between these two modification events exists to govern Isw1 function. Mutagenesis studies of acetylation and ubiquitination sites revealed that the acetylation status of Isw1K97 coordinates with its ubiquitination processes at Isw1K113 and Isw1K441 through modulating the interaction between Isw1 and Cdc4, an E3 ligase. Additionally, clinical isolates of C. neoformans overexpressing the degradation-resistant ISW1K97Q allele showed impaired drug-resistant phenotypes. Collectively, our studies revealed a sophisticated acetylation-Isw1-ubiquitination regulation axis that controls multidrug resistance in C. neoformans.

microbiology↗

bioRxiv2022

Decoding the Variant-to-Function Relationship for LIPA, a Risk Locus for CAD

Translating human genomic discoveries into mechanistic insights requires linking genetic variations to candidate genes and their causal functional phenotypes. Genome-wide association studies have consistently identified LIPA as a risk locus for coronary artery disease (CAD), with previous expression quantitative trait loci (eQTL) analyses prioritizing LIPA as a candidate causal gene. However, functional studies elucidating the causal variants, regulatory mechanisms, target cell types, and their causal impact on atherosclerosis have been lacking. To address this gap, we applied functional genomics and experimental mouse models to establish the variant-to-function relationship at the LIPA locus. Our findings show that CAD risk alleles in the LIPA locus increase LIPA expression and enzyme activity specifically in monocytes/macrophages by enhancing PU.1 binding to an intronic enhancer region that interacts with the LIPA promoter. In myeloid Lipa-overexpressing mice, we observed larger atherosclerotic lesions accompanied by altered macrophage function, including increased macrophage accumulation due to enhanced monocyte recruitment, reduced neutral lipid accumulation, and upregulation of integrin and extracellular matrix pathways. Our work establishes a direct causal link between LIPA risk alleles and increased monocyte/macrophage LIPA that exacerbates atherosclerosis, bridging human functional genomic evidence to the mechanistic understanding of CAD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=58 SRC="FIGDIR/small/516293v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11ce287org.highwire.dtl.DTLVardef@15c201aorg.highwire.dtl.DTLVardef@13f90c9org.highwire.dtl.DTLVardef@3aa3be_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗