Biology subjects

Lin, J.

Publications and source records attributed to Lin, J..

At least 235 records · Page 13Linked to original sources

bioRxiv2023

Distinct Microstructural Heterogeneities Underpin Specific Micromechanical Properties in Human ACL Femoral and Tibial Entheses

The anterior cruciate ligament (ACL) is anchored to the femur and tibia by a specialized interface tissue called the enthesis, which transfers forces in multiple directions and magnitudes without accruing fatigue damage during loading cycles over a lifetime. However, the precise structural and mechanical characteristics of the ACL femoral enthesis (FE) and tibial enthesis (TE) and their intricate interplay are unknown. In this study, we identified two ultrathin-graded mineralization regions in the FE ([~]21 m) and TE ([~]14 m), both of which exhibited distinct biomolecular compositions and mineral assembly patterns. FE interface exhibited progressively maturing hydroxyapatites (HAps), whereas minerals at the TE interface region changed from an amorphous phase (ACP) to HAps with increasing crystallinity. The LC-MS/MS results revealed that MGP protein uniquely enriched at the TE interface may be favorable for stabilizing ACP, while CLEC11A enriched at the FE interface could facilitate osteogenesis of the interface. The finite element analysis results indicated that the FE model was more resistant to shearing, while the TE model facilitated tensile resistance. It suggested that the great discrepancy in biomolecular expression and the corresponding mineral assembling heterogeneities together contributed to the superior mechanical properties of both the FE and TE models. These findings provide new perspectives regarding the management of ACL injury and the development of high-performance interface materials.

bioengineering↗

bioRxiv2023

weIMPUTE: A User-Friendly Web-Based Genotype Imputation Platform

Genotype imputation is a critical preprocessing step in genome-wide association studies (GWAS), enhancing statistical power for detecting associated single nucleotide polymorphisms (SNPs) by increasing marker size. In response to the needs of researchers seeking user-friendly graphical tools for imputation without requiring informatics or computer expertise, we have developed weIMPUTE, a web-based imputation graphical user interface (GUI). Unlike existing genotype imputation software, weIMPUTE supports multiple imputation software, including SHAPEIT, Eagle, Minimac4, Beagle, and IMPUTE2, while encompassing the entire workflow, from quality control to data format conversion. This comprehensive platform enables both novices and experienced users to readily perform imputation tasks. For reference genotype data owners, weIMPUTE can be installed on a server or workstation, facilitating web-based imputation services without data sharing. weIMPUTE represents a versatile imputation solution for researchers across various fields, offering the flexibility to create personalized imputation servers on different operating systems.

bioinformatics↗

bioRxiv2023

A genomic exploration of the possible de-extirpation of the Zanzibar leopard

The recently extirpated Zanzibar leopard was the only known African leopard (Panthera pardus spp.) population restricted exclusively to a major island habitat. Although its demise was driven through habitat change and conflict with humans, given its role as a keystone species for the Zanzibar Archipelago, its potential reintroduction might offer a means for helping preserve the natural biodiversity of its former habitat. Whether this is feasible, however, would be contingent on both whether closely related source populations can be identified on mainland Africa, and whether the Zanzibar form exhibited any special adaptations that might need to be considered when choosing such a source. In light of these questions, we genomically profiled two of the six known historic specimens, to explore whether they represent a realistic candidate for de-extirpation through reintroduction. Our analyses indicate that despite its geographic separation, the Zanzibar leopard shared a close genetic relationship with mainland East African individuals. Furthermore, although its uniqueness as an island population was emphasised by genomic signatures of high inbreeding and increased mutation load, the latter similar to the level of the critically endangered Amur leopard (P. p. orientalis), we find no evidence of positive selection unique to Zanzibar. We therefore conclude that should attempts to restore leopards to Zanzibar be planned, then mainland East African leopards would provide a suitable gene pool, whether using genetic engineering or conventional rewilding approaches.

evolutionary biology↗

bioRxiv2023

Non-cell autonomous cardiomyocyte regulation complicates gene supplementation therapy for LMNA cardiomyopathy

AimsRecombinant adeno-associated viruses (rAAVs) are federally approved gene delivery vectors for in vivo gene supplementation therapy. Loss-of-function truncating variants of LMNA, the coding gene for Lamin-A/C, are one of the primary causes of inherited dilate cardiomyopathy (DCM). Here we aim to study whether AAV-based LMNA supplementation could treat LMNA deficiency-triggered cardiac defects. Methods and ResultsWe compared whole-body, cardiomyocyte-specific and genetic-mosaic mouse models that carry Lmna truncating variants at the same genetic loci and uncovered primarily a non-cell autonomous impact of Lmna on cardiomyocyte maturation. Whole-body lamin-A supplementation by rAAVs moderately rescued the cardiac defects in Lmna germline mutants. By contrast, cardiomyocyte-specific lamin-A addback failed to restore the cardiomyocyte growth defects. A Cre-loxP-based AAV vector that expresses lamin-A throughout the body but excluding the heart was able to restore cardiomyocyte growth in Lmna germline mutants. ConclusionsLmna regulates cardiomyocyte growth non-cell autonomously. Non-myocytes are the key cell targets for a successful gene therapy for LMNA-associated cardiac defects. Translational perspectiveLMNA truncating mutations are among the major causes of inherited DCM. AAV gene supplementation therapy is emerging as a promising strategy to treat genetic cardiomyopathy, but whether this strategy is suitable for LMNA cardiomyopathy remained unclear. Our study counterintuitively showed that the cardiomyocytes are not necessarily the correct therapeutic cell targets for AAV-based treatment of LMNA cardiomyopathy. By contrast, careful elucidation of cell-autonomous versus non-cell-autonomous gene functions is essential for the proper design of a gene supplementation therapy for cardiomyopathy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/549413v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@37cfdaorg.highwire.dtl.DTLVardef@2f2cd1org.highwire.dtl.DTLVardef@1278d08org.highwire.dtl.DTLVardef@19c4869_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Distinct Conformations of Mirabegron Determined by MicroED

Mirabegron, commonly known as "Myrbetriq", has been widely prescribed as a medicine for overactive bladder syndrome for over a decade. However, the structure of the drug and what conformational changes it may undergo upon binding its receptor remain unknown. In this study, we employed microcrystal electron diffraction (MicroED) to reveal its elusive three-dimensional (3D) structure. We find that the drug adopts two distinct conformational states (conformers) within the asymmetric unit. Analysis of hydrogen bonding and packing demonstrated that the hydrophilic groups were embedded within the crystal lattice, resulting in a hydrophobic surface and low water solubility. Structural comparison revealed the presence of trans- and cis-forms in conformers 1 and 2, respectively. Comparison of the structures of Mirabegron alone with that of the drug bound to its receptor,1 the beta 3 adrenergic receptor ({beta}3AR) suggests that the drug undergoes major conformational change to fit in the receptor agonist binding site. This research highlights the efficacy of MicroED in determining the unknown and polymorphic structures of active pharmaceutical ingredients (APIs) directly from powders.

biochemistry↗

bioRxiv2023

Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia

Epigenetic regulators present novel opportunities for both ischemic stroke research and therapeutic interventions. While previous work has implicated that they may provide neuroprotection by potentially influencing coordinated sets of genes and pathways, most of them remains largely uncharacterized in ischemic conditions. In this study, we used the oxygen-glucose deprivation (OGD) model in the immortalized mouse hippocampal neuronal cell line HT-22 and carried out an RNAi screen on epigenetic regulators. We identified Prmt5 as a novel negative regulator of neuronal cell survival after OGD, which presented a phenotype of translocation from the cytosol to the nucleus upon oxygen and energy depletion both in vitro and in vivo. Prmt5 bound to the chromatin and a large number of promoter regions to repress downstream gene expression. Silencing Prmt5 significantly dampened the OGD-induced changes for a large-scale of genes, and gene ontology analysis showed that Prmt5-target genes were highly enriched for Hedgehog signaling. Encouraged by the above observation, we treated mice with middle cerebral artery occlusion (MCAO) with the Prmt5 inhibitor EPZ015666 and found that Prmt5 inhibition sustain protection against neuronal death in vivo. Together, our findings revealed a novel epigenetic mechanism of Prmt5 in cerebral ischemia and uncovered a potential target for neuroprotection.

cell biology↗

bioRxiv2023

Global changes in open reading frame dominance of RNAs during cancer initiation and progression

Cancer cells express unique RNA transcripts; however, the factors determining their translation have remained unclear. We recently developed open reading frame (ORF) dominance as a measure that correlates with coding potential of RNAs. Upon calculating the ORF dominance of cancer-specific transcripts across 24 human tumor types, 14 exhibited significantly higher ORF dominance in cancer than in normal tissues. In organoid-based mouse genetic models, ORF dominance increased with carcinogenesis. Gene ontology analysis revealed that gene sets with increased ORF dominance were associated with cell proliferation, while those with decreased ORF dominance were linked to DNA damage response. Translatome analyses demonstrated that elevated ORF dominance during carcinogenesis resulted in higher translation frequencies of ribosome-bound RNAs. As cancer progressed, ORF dominance showed that the boundary between coding and noncoding transcripts became blurred prior to distant metastasis, indicating decreased proliferative cell populations and increased generation of RNA isoforms that potentially translate neoantigens before the development of metastatic tumors. These findings suggest that cancer evolution leads to dynamic changes in ORF dominance, resulting in global translational alterations in transcriptomes.

cancer biology↗

bioRxiv2023

Epidermal Growth Factor potentiates EGFR(Y992/1173)-mediated therapeutic response of triple negative breast cancer cells to cold atmospheric plasma-activated medium

Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment that selectively kills basal-like breast cancer cells. We used CAP-activated media (PAM) to capture the multi-modal chemical species of CAP. Specific antibodies, small molecule inhibitors and CRISPR/Cas9 gene-editing approaches showed an essential role for receptor tyrosine kinases, especially epidermal growth factor (EGF) receptor, in mediating triple negative breast cancer (TNBC) cell responses to PAM. EGF also dramatically enhanced the sensitivity and specificity of PAM against TNBC cells. Site-specific phospho-EGFR analysis, signal transduction inhibitors and reconstitution of EGFR-depleted cells with EGFR-mutants confirmed the role of phospho-tyrosines 992/1173 and phospholipase C gamma signaling in upregulating levels of reactive oxygen species above the apoptotic threshold. EGF-triggered EGFR activation enhanced the sensitivity and selectivity of PAM effects on TNBC cells, such that a strategy based on the synergism of CAP and EGF therapy may provide new opportunities to improve the clinical management of TNBC.

cancer biology↗

bioRxiv2023

Human-specific lncRNAs contributed critically to human evolution by distinctly regulating gene expression

What genes and regulatory sequences critically differentiate modern humans from apes and archaic humans, which share highly similar genomes but show distinct phenotypes, has puzzled researchers for decades. Previous studies examined species-specific protein-coding genes and related regulatory sequences, revealing that birth, loss, and changes in these genes and sequences can drive speciation and evolution. However, investigations of species-specific lncRNA genes and related regulatory sequences, which regulate substantial genes, remain limited. We identified human-specific (HS) lncRNAs from GENCODE-annotated human lncRNAs, predicted their DNA binding domains (DBDs) and binding sites (DBSs), analyzed DBS sequences in modern humans (CEU, CHB, and YRI), archaic humans (Altai Neanderthals, Denisovans, and Vindija Neanderthals), and chimpanzees, and investigated how HS lncRNAs and their DBSs have influenced gene expression in archaic and modern humans. Our results suggest that these lncRNAs and DBSs have substantially reshaped gene expression. This reshaping has evolved continuously from archaic to modern humans, enabling humans to adapt to new environments and lifestyles, promoting brain evolution, and resulting in cross-population differences. The parallel analysis of gene expression in GTEx tissues by HS TFs and their DBSs indicates that HS lncRNAs have reshaped gene expression in the brain more significantly than HS TFs.

genomics↗

bioRxiv2023

Fingering instability accelerates population growth of an expanding cell collective

During the expansion of a cell collective, such as the development of microbial colonies and tumor progression, the local cell growth increases the local pressure, which in turn suppresses cell growth. How this pressure-growth coupling affects the expansion of a cell collective remains unclear. Here, we answer this question using a continuum model of cell collective. We find that a fast-growing leading front and a slow-growing interior of the cell collective emerge due to the pressure-dependent growth rate. The leading front can exhibit fingering instability and we confirm the predicted instability criteria numerically with the leading front explicitly simulated. Intriguingly, we find that fingering instability is not only a consequence of local cell growth but also enhances the entire populations growth rate as positive feedback. Our work unveils the fitness advantage of fingering formation quantitatively and suggests that the ability to form protrusion can be evolutionarily selected.

biophysics↗

bioRxiv2023

Ripening and synchronization of biomolecular condensates in a heterogeneous elastic medium

Biomolecular condensates play a crucial role in regulating gene expression, but their behavior in chromatin remains poorly understood. Classical theories of phase separation are limited to thermal equilibrium, and traditional methods can only simulate a limited number of condensates. In this paper, we introduce a novel mean-field-like method that allows us to simulate millions of condensates in a heterogeneous elastic medium to model the dynamics of transcriptional condensates in chromatin. Using this method, we unveil an elastic ripening process in which the average condensate radius exhibits a unique temporal scaling, [<]R[>] [~] t1/5, different from the classical Ostwald ripening, and we theoretically derive the exponent based on energy conservation and scale invariance. We also introduce active dissolution to model the degradation of transcriptional condensates upon RNA accumulation. Surprisingly, three different kinetics of condensate growth emerge, corresponding to constitutively expressed, transcriptional-bursting, and silenced genes. Notably, multiple distributions of transcriptional-bursting kinetics from simulations, e.g., the burst frequency, agree with transcriptome-wide experimental data. Furthermore, the timing of growth initiation can be synchronized among bursting condensates, with power-law scaling between the synchronization period and dissolution rate. Our results shed light on the complex interplay between biomolecular condensates and the elastic medium, with important implications for gene expression regulation.

biophysics↗

bioRxiv2023

Analyzing bivariate cross-trait genetic architecture in GWAS summary statistics with the BIGA cloud computing platform

As large-scale biobanks provide increasing access to deep phenotyping and genomic data, genome-wide association studies (GWAS) are rapidly uncovering the genetic architecture behind various complex traits and diseases. GWAS publications typically make their summary-level data (GWAS summary statistics) publicly available, enabling further exploration of genetic overlaps between phenotypes gathered from different studies and cohorts. However, systematically analyzing high-dimensional GWAS summary statistics for thousands of phenotypes can be both logistically challenging and computationally demanding. In this paper, we introduce BIGA (https://bigagwas.org/), a website that aims to offer unified data analysis pipelines and processed data resources for cross-trait genetic architecture analyses using GWAS summary statistics. We have developed a framework to implement statistical genetics tools on a cloud computing platform, combined with extensive curated GWAS data resources. Through BIGA, users can upload data, submit jobs, and share results, providing the research community with a convenient tool for consolidating GWAS data and generating new insights.

genetics↗

bioRxiv2023

Improving the solubility of pseudo-hydrophobic Alzheimer's Disease medicinal chemicals through co-crystal formulation

Natural products are ligands and potential inhibitors of Alzheimers disease (AD) tau. Dihydromyricetin (DHM) is a CNS active natural product. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH allowing formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All salt formulations show better inhibitory activity against AD tau than the non-salt form, with efficacies correlating to enhanced solubilities. These results underscore the role of structural chemistry in guiding selection of solubilizing agents for chemical formulation. We propose DHM salts are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding. Additionally, DHM is a suitable lead for medicinal chemistry and possible development of CNS pharmaceuticals.

pharmacology and toxicology↗

bioRxiv2023

Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex

Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy. Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes. We identified that SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and SPEG deficiency results in myospryn complex abnormalities. In addition, transcriptional and protein profiles of SPEG-deficient muscle revealed defective mitochondrial function including aberrant accumulation of enlarged mitochondria on electron microscopy. Furthermore, SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. On analyzing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction and peroxisome proliferator-activated receptors signaling, which may be due to defective triad and mitochondrial abnormalities. In summary, we have elucidated the critical role of SPEG in triad as it works closely with myospryn complex, phosphorylates JPH2 and RyR1, and demonstrated that its deficiency is associated with mitochondrial abnormalities. This study emphasizes the importance of using multi-omics techniques to comprehensively analyze the molecular anomalies of rare diseases. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/538136v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@bc3cbborg.highwire.dtl.DTLVardef@37195dorg.highwire.dtl.DTLVardef@1624caeorg.highwire.dtl.DTLVardef@985a2c_HPS_FORMAT_FIGEXP M_FIG C_FIG We have previously linked mutations in SPEG (striated preferentially expressed protein) with a recessive form of centronuclear myopathy and/or dilated cardiomyopathy and have characterized a striated muscle-specific SPEG-deficient mouse model that recapitulates human disease with disruption of the triad structure and calcium homeostasis in skeletal muscles. In this study, we applied multi-omics approaches (interactomic, proteomic, phosphoproteomic, and transcriptomic analyses) in the skeletal muscles of SPEG-deficient mice to assess the underlying pathways associated with the pathological and molecular abnormalities. O_LISPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and its deficiency results in myospryn complex abnormalities. C_LIO_LISPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. C_LIO_LISPEG and SPEG{beta} have different interacting partners suggestive of differential function. C_LIO_LITranscriptome analysis indicates dysregulated pathways of ECM-receptor interaction and peroxisome proliferator-activated receptor signaling. C_LIO_LIMitochondrial defects on the transcriptome, proteome, and electron microscopy, may be a consequence of defective calcium signaling. C_LI

molecular biology↗

bioRxiv2023

WNT2B Deficiency Causes Increased Susceptibility to Colitis in Mice and Impairs Intestinal Epithelial Development in Humans

Background and aimsWNT2B is a canonical Wnt ligand previously thought to be fully redundant with other Wnts in the intestinal epithelium. However, humans with WNT2B deficiency have severe intestinal disease, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. MethodsWe investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the impact of inflammatory challenge to the small intestine, using anti-CD3{chi} antibody, and to the colon, using dextran sodium sulfate (DSS). In addition, we generated human intestinal organoids (HIOs) from WNT2B-deficient human iPSCs for transcriptional and histological analyses. ResultsMice with WNT2B deficiency had significantly decreased Lgr5 expression in the small intestine and profoundly decreased expression in the colon, but normal baseline histology. The small intestinal response to anti-CD3{chi} antibody was similar in Wnt2b KO and wild type (WT) mice. In contrast, the colonic response to DSS in Wnt2b KO mice showed an accelerated rate of injury, featuring earlier immune cell infiltration and loss of differentiated epithelium compared to WT. WNT2B-deficient HIOs showed abnormal epithelial organization and an increased mesenchymal gene signature. ConclusionWNT2B contributes to maintenance of the intestinal stem cell pool in mice and humans. WNT2B deficient mice, which do not have a developmental phenotype, show increased susceptibility to colonic injury but not small intestinal injury, potentially due to a higher reliance on WNT2B in the colon compared to the small intestine. WNT2B deficiency causes a developmental phenotype in human intestine with HIOs showing a decrease in their mesenchymal component and WNT2B-deficient patients showing epithelial disorganization. Data Transparency StatementAll RNA-Seq data will be available through online repository as indicated in Transcript profiling. Any other data will be made available upon request by emailing the study authors.

molecular biology↗

bioRxiv2023

Use of a human small airway epithelial cell line to study the interactions of Aspergillus fumigatus with pulmonary epithelial cells

During the initiation of invasive aspergillosis, inhaled Aspergillus fumigatus conidia are deposited on the epithelial cells lining the bronchi, terminal bronchioles, and alveoli. While the interactions of A. fumigatus with bronchial and type II alveolar cell lines have been investigated in vitro, little is known about the interactions of this fungus with terminal bronchiolar epithelial cells. We compared the interactions of A. fumigatus with the A549 type II alveolar epithelial cell line and the HSAEC1-KT human small airway epithelial (HSAE) cell line. We found that A. fumigatus conidia were poorly endocytosed by A549 cells, but avidly endocytosed by HSAE cells. A. fumigatus germlings invaded both cell types by induced endocytosis, but not by active penetration. A549 cell endocytosis of A. fumigatus was independent of fungal viability, more dependent on host microfilaments than microtubules, and induced by A. fumigatus CalA interacting with host cell integrin 5{beta}1. By contrast, HSAE cell endocytosis required fungal viability, was more dependent on microtubules than microfilaments, and did not require CalA or integrin 5{beta}1. HSAE cells were more susceptible than A549 cells to damage caused by direct contact with killed A. fumigatus germlings and by secreted fungal products. In response to A. fumigatus infection, A549 cells secreted a broader profile of cytokines and chemokines than HSAE cells. Taken together, these results demonstrate that studies of HSAE cells provide complementary data to A549 cells and thus represent a useful model for probing the interactions of A. fumigatus with bronchiolar epithelial cells in vitro. ImportanceDuring the initiation of invasive aspergillosis, Aspergillus fumigatus invades, damages, and stimulates the epithelial cells that line the airways and alveoli. Previous studies of A. fumigatus- epithelial cell interactions in vitro have used either large airway epithelial cell lines or the A549 type II alveolar epithelial cell line. The interactions of fungi with terminal bronchiolar epithelial cells have not been investigated. Here, we compared the interactions of A. fumigatus with A549 cells and the Tert-immortalized human small airway epithelial HSAEC1-KT (HSAE) cell line. We discovered that A. fumigatus invades and damages these two cell lines by distinct mechanisms. Also, the proinflammatory responses of the cell lines to A. fumigatus are different. These results provide insight into how A. fumigatus interacts with different types of epithelial cells during invasive aspergillosis and demonstrate that HSAE cells are useful in vitro model for investigating the interactions of this fungus with bronchiolar epithelial cells.

microbiology↗

bioRxiv2023

A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis

Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic-metabolic feedback loop between the epithelial-mesenchymal transition (EMT) transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation to drive breast cancer metastasis. Functionally, Depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LD) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2 activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and lipid droplet accumulation but also enhances fatty acid oxidation (FAO) and ATP production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LD storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2-ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis. HighlightsZEB2 activates FAO through transcription of ACSL4 ACSL4 regulates lipid metabolism through FAO, promoting breast cancer metastasis Targeting ZEB2-ACSL4 signaling axis inhibits breast cancer metastasis SignificanceWe describe a novel positive feedback loop between ZEB2 and ACSL4 that results in enhanced cellular lipid storage and FA oxidation to drive breast cancer metastasis.

cancer biology↗

bioRxiv2023

Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia

The COVID-19 pandemic continues to be a health crisis with major unmet medical needs. The early responses from airway epithelial cells, the first target of the virus regulating the progression towards severe disease, are not fully understood. Primary human air-liquid interface cultures representing the broncho-alveolar epithelia were used to study the kinetics and dynamics of SARS-CoV-2 variants infection. The infection measured by nucleoprotein expression, was a late event appearing between day 4-6 post infection for Wuhan-like virus. Other variants demonstrated increasingly accelerated timelines of infection. All variants triggered similar transcriptional signatures, an "early" inflammatory/immune signature preceding a "late" type I/III IFN, but differences in the quality and kinetics were found, consistent with the timing of nucleoprotein expression. Response to virus was spatially organized: CSF3 expression in basal cells and CCL20 in apical cells. Thus, SARS-CoV-2 virus triggers specific responses modulated over time to engage different arms of immune response.

immunology↗