Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 343 records · Page 19Linked to original sources

bioRxiv2024

The Cryo-EM structure of TRPC1 and TRPC5 heterotetramer

Ion channel heteromers display distinct electrophysiological and ligand-binding properties, allowing precise modulation of cellular functions in specific tissues. Among the TRPC subtypes, the TRPC1/4/5 heteromers are the most abundant isoform in the human brain and represent a primary target for treating anxiety and depression. However, the structural organization of TRPC1/4/5 heteromers remain unclear, limiting the advancement of research on these channels. Here, we report the cryo-EM structure of TRPC1/5 heterotatramer at a resolution of 2.84 [A]. It consists of an asymmetric structure with three TRPC5 subunits and one TRPC1 subunit. Further structural and functional analysis revealed that the TRPC1 subunit contributes to an asymmetrical ion conduction pathway, a characteristic that differentiates it from TRPC5 homomers. The unique features of the TRPC1 pore loop and its interface interactions with TRPC5 were shown to play crucial roles in modulating the ion conduction properties and gating mechanisms of the heteromeric complex. In addition, we identified key residues within the gating regions that influence channel activation and ion permeability, elucidating the structural basis for the functional divergence between the TRPC1/C5 heterotetramer and TRPC5 homotetramer. Notably, TRPC5 residues were found to dominate gating mechanisms, underscoring the complex interplay between subunit composition and functional outcomes in TRPC channels. Our findings provide novel insights into the structural and functional dynamics of TRPC1/C5 heteromers, paving the way for targeted therapeutic strategies in TRPC5-related disorders.

biophysics↗

bioRxiv2024

Robust fine-mapping in the presence of linkage disequilibrium mismatch

Fine-mapping methods based on summary statistics from genome-wide association studies (GWAS) and linkage disequilibrium (LD) information are widely used to identify potential causal variants. However, LD mismatch between the external LD reference panel and the GWAS population is common and can lead to compromised accuracy of fine-mapping. We developed RSparsePro, a probabilistic graphical model with an efficient variational inference algorithm, to perform robust fine-mapping in the presence of LD mismatch. In simulation studies with a varying degree of LD mismatch, RSparsePro identified credible sets with a consistently higher power and coverage than SuSiE. In fine-mapping cis-protein quantitative trait loci, RSparsePro identified credible sets with a consistently higher enrichment of variants with functional impacts and cross-study replication rates. In fine-mapping risk loci for low-density lipoprotein cholesterol in ancestry-specific GWAS, RSparsePro identified biologically relevant variants in drug target genes and implicated potential regulatory mechanisms. RSparsePro is openly available at https://github.com/zhwm/RSparsePro_LD.

bioinformatics↗

bioRxiv2024

CILP from Cartilage Intermediate Zone Inhibits Hyaline Cartilage Fibrosis and Chondrocyte Ferroptosis via Keap1-Nrf2 Axis in Early Osteoarthritis Exercise Therapy

By analyzing the single-cell RNA-Seq libraries, the roles of cartilage intermediate layer protein (CILP) and the cartilage intermediate zone in early osteoarthritis (OA) exercise therapy were explored. An early OA rat model was established via a 4-week anterior cruciate ligament transection. The effect of moderate exercise was confirmed using histology, the open-field test, and gait analysis. The response of the cartilage intermediate zone to mechanical stimulation was explored using multiplex fluorescent immunohistochemical staining. Radiomics was used to evaluate the relatively damaged and undamaged areas in the cartilage of patients with OA. CILP was OE and KD in early OA chondrocytes, and quantitative proteomics, yeast one-hybrid, co-immunoprecipitation, Nrf2 and ubiquitination assays were used to investigate its mechanism. We found that moderate exercise upregulates CILP in the cartilage intermediate zone. CILP recovers the type II/I collagen, Sox9, and -SMA expression ratios, and reduces Keap1-Nrf2 dimer stability, inhibiting Nrf2 ubiquitination and promoting Nrf2 nuclear translocation. Nrf2 nuclear translocation activates SLC7A11, HO-1, GPX4, and SOD-1 expression, decreases MDA content, and increases GSH content, inhibiting chondrocyte ferroptosis and promoting fibrocartilage hyalinization. In conclusion, the exercise-induced cartilage intermediate zone and CILP-Keap1-Nrf2 axis inhibit hyaline cartilage fibrosis and chondrocyte ferroptosis to alleviate early OA.

cell biology↗

bioRxiv2024

Revolutionizing large-scale DNA synthesis with microchip-based massive in parallel synthesis system

DNA synthesis serves as the fundamental enabling technology of engineering biology, aiming to provide DNA molecules of designed composition, length, and complexity at scale and low cost. Current high-throughput DNA synthesis technologies rely on intricate chip manufacturing and microfluidic systems to provide large-scale synthetic oligonucleotides, at the expense of low concentration and limited compatibility in the processing of longer DNA constructs assembly. Here, we report a microchip-based massive in parallel synthesis (mMPS), pioneering an "identification-sorting-synthesis-recycling" iteration mechanism to microchips for high throughput DNA synthesis. In comparison to microarray-based methods, we demonstrate that our method can increase the DNA product concentration by 4 magnitudes (to picomole-scale per sequence) and greatly simplifies the downstream processes for large-scale gene synthesis construction. By the construction of 1.97 million-diversity variant libraries that cover 1,254 human protein domains, we demonstrated the uniformity of the constructed variant libraries using mMPS-derived oligos is greatly improved, with amino acid distribution highly consistent as designed. In addition, by synthesizing 285 1kb-to-3kb genes with varying degrees of sequence complexity from previously reported strains A501 and 3DAC, potential ancestor of early archaea and bacteria, our result shows that the overall gene assembly success rate using mMPS-derived oligos is increased by 10-fold in comparison to other methods. Our mMPS technology holds the potential to close the gap between the quality and cost of writing DNA in increasing demand across many sectors of research and industrial activities.

synthetic biology↗

bioRxiv2024

PhenoScreen: A Dual-Space Contrastive Learning Framework-based Phenotypic Screening Method by Linking Chemical Perturbations to Cellular Morphology

Phenotypic drug discovery (PDD) screens compounds in cellular models that represent disease-relevant phenotypes, offering a compelling alternative to traditional target-based approaches. Unlike conventional methods, where compounds act on a single predefined target, PDD identifies compounds capable of exerting therapeutic effects through multiple targets and mechanisms. This makes PDD particularly valuable for discovering first-in-class drugs, especially for diseases with poorly understood molecular mechanisms or those lacking validated therapeutic targets. By enabling broader exploration of biological systems and uncovering multi-target drugs (polypharmacology), PDD provides a powerful strategy for tackling complex diseases. In this study, we introduce PhenoScreen, a deep learning framework designed to advance PDD by utilizing large-scale compound-phenotype association data. Through contrastive learning, PhenoScreen connects chemical space with cellular morphological profiles, allowing for accurate prediction of compound-induced phenotypic changes. PhenoScreen can also accurately identfiy lead compounds which could induce user defined phenotypic shift but more novel scaffolds using different levels of phenotypic information reflected by diverse compounds. The model was validated across multiple screening tasks and successfully predicted active compounds inducing user-specified phenotypes with varying inhibitory effects in the osteosarcoma phenotypic model. Further, other than showing effectiveness to osteosarcoma, our experiments also showed that PhenoScreen demonstrated strong generalization to rhabdomyosarcoma, and the active compound we screened had an IC50 of up to 1.842 M, suggesting its ability to capture key phenotypic features shared across cancer cells. These results underscore PhenoScreens potential to accelerate drug discovery by identifying novel therapeutic pathways and increasing the diversity of viable drug candidates. PhenoScreen is accessible online via our groups web server for compound virtual screening at https://bailab.siais.shanghaitech.edu.cn/services/PhenoScreen/, and the source codes are available at https://github.com/Shihang-Wang-58/PhenoScreen.

bioinformatics↗

bioRxiv2024

SPP1+ tumor-associated macrophages induce radioresistance of nasopharyngeal carcinoma through crosstalk with the tumor microenvironment

The function and phenotype of tumor-associated macrophages (TAMs) influence the efficacy of radiotherapy. However, the effect of different subsets of TAMs on the radioresistance in nasopharyngeal carcinoma (NPC) still needs to be further explored. This study utilized single-cell RNA sequencing (scRNA-seq) to analyze 120,579 cells obtained from 15 NPC samples. Cell annotation, cell-cell communication analysis, and functional annotation were used to investigate the impact of TAMs on the effectiveness of radiotherapy in NPC patients. Additionally, we employed RNA-seq data and clinical information from many patients, including 24 NPC samples from Zhujiang Hospital, 3,934 samples from patients with a history of radiotherapy, for further validation. We identified a hub TAM subpopulation, SPP1+ TAMs, that induced radioresistance in NPC based on single-cell RNA sequencing (scRNA-seq) data. We combined many public datasets to confirm their prognostic value in radiotherapy patients. We found that SPP1+ TAMs had stronger protumorigenic and immunosuppressive effects in the postradiotherapy recurrent tumor (PRRT) group. SPI1 transcription factor efficiently regulates the expression level of SPP1 in macrophages. In addition, we validated the underlying mechanisms by molecular docking, multiplex immunofluorescence and cellular experiments. In conclusions, by forming an immunosuppressive microenvironment and promoting tumor cell proliferation, SPP1+ TAMs leading to radioresistance and poor clinical prognosis in NPC patients. Targeting SPP1+ TAMs could provide new insights into improving the efficacy of radiotherapy in NPC patients.

cancer biology↗

bioRxiv2024

Birds migrate longitudinally in response to the resultant Asian monsoons of the Qinghai-Tibet Plateau uplift

The uplift of the Qinghai-Tibet Plateau is one of the greatest geological events on Earth, pivotally shaping biogeographic patterns across continents, especially for migratory species that need to overcome topographical barriers to fulfil their annual circle. However, how the uplift influences animal migration strategies remains largely unclear. We compare the current flyways of 50 avian species migrating across the plateau with those reconstructed before the uplift as a counterfactual. We find that the major effect of the plateau uplift is changing avian migratory directions from the latitudinal to the longitudinal. The monsoon system generated by the uplift rather than the high elevation per se shapes those changes. These findings unveil how an important global geological event has influenced biogeographic patterns of migratory birds, yielding testable hypotheses for how observed avian distributions emerge.

ecology↗

bioRxiv2024

NSD2 promotes cell durotaxis and drives the transition from PKD to tubulocystic renal cell carcinoma through integrin/FAK/AKT signaling

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. NSD2 is an H3K36-specific di-methyltransferase which has been reported to participate in diverse biological processes and human tumors. However, its role in RCC remains unclear. Here, we found that NSD2 is highly expressed in RCC, which is associated with poor survival in RCC patients. NSD2 facilitates the transition from Myc-induced polycystic kidney disease to tubulocystic renal cell carcinoma (TCRCC), which is a rare RCC subtype with distinctive clinicopathologic and genetic characterizations. The mice with kidney-specific overexpression of MYC and NSD2 (KMN) display severe cyst burden at only 6 weeks of age, and develop into TCRCC at 12 weeks of age. Mechanistically, NSD2 transcriptionally upregulates the expressions of integrins (Itga4 and Itga11), to further activate the FAK/AKT pathway. In addition, we found that NSD2 enhances the cell proliferation on the stiff matrix of PEGDA hydrogel. Moreover, inhibition of FAK signaling relieves the symptoms of KMN mice, and significantly rescues the enhanced cell proliferation caused by NSD2 overexpression in vitro. Together, our findings highlight an epigenetic mechanism by which NSD2 regulates TCRCC tumorigenesis through the integrin/FAK/AKT pathway. This study may also pave the way for the development of targeted, patient-tailored therapies for TCRCC patients with NSD2 amplification or high expression.

cancer biology↗

bioRxiv2024

Deficiency of Hv1 Proton Channel Enhances Macrophage Antigen Presentation and Anti-Tumor Responses in Glioma

In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword--they are a major cellular component modulating the immune response while presenting a potential therapeutic target. Our study highlights the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a crucial regulator of their physiological functions. We discovered a strong correlation between increased Hv1 expression and poor prognosis in glioblastoma patients. Depleting Hv1 significantly extended survival in a mouse model of glioma. Employing multiple novel transgenic mouse lines, we demonstrated that Hv1 is upregulated in response to tumor presence, with glioma-associated macrophages as the principal contributors. Specifically, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a combination of in vivo two-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we found that Hv1 depletion leads to reduced macrophage infiltration and enhanced antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma.

neuroscience↗

bioRxiv2024

Benchmarking Bayesian colocalization methods in validating Mendelian randomization-based target discoveries from circulating proteins for cardiometabolic diseases

Mendelian randomization (MR) is an important tool for identifying potential biomarkers and drug targets. Colocalization analysis is crucial for validating MR findings and guarding against confounding due to linkage disequilibrium. We aim to benchmark the performance of four Bayesian colocalization methods in validating MR-based target discoveries from circulating proteins for cardiometabolic traits. We assessed the associations between circulating levels of 1,535 proteins and five cardiometabolic traits, followed by colocalization analyses using coloc, coloc+SuSiE, PWCoCo and SharePro. All methods demonstrated well-controlled false discoveries. SharePro demonstrated the highest frequency in supporting 160 (79.6%) of the 201 Bonferroni-significant protein-trait associations identified by MR, compared to coloc (supporting 40.3% of these associations), coloc+SuSiE (46.8%), and PWCoCo (45.8%), and was robust to varying prior colocalization probabilities. Protein-trait associations supported by SharePro were more likely to agree with significant gene-level associations identified in exome-wide association studies and implicate known drug targets. Eight protein-trait associations were exclusively supported by SharePro, suggesting potential cardiometabolic biomarkers or drug targets, such as HSF1 and HAVCR2. In summary, SharePro most often supports statistically significant associations identified through MR for cardiometabolic traits. Combining multiple lines of evidence using different methods may substantially increase the yield of biomarker and drug target discovery programs.

genetics↗

bioRxiv2024

Small-molecule Activation of TFEB Alleviates Niemann-Pick Disease Type C via Promoting Lysosomal Exocytosis and Biogenesis

Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists ie SFN as potential NPC therapeutic candidates.

molecular biology↗

bioRxiv2024

Nrf2 orchestrates epigenetic regulations and serves as the master regulator of KLF4 expression and activity during arsenic-induced transformation

Emerging evidence suggests that Nrf2 plays a pro-carcinogenic role in cancer. Our previous study showed that arsenic-induced Nrf2 activation triggers metabolic reprogramming, leading to the formation of cancer stem-like cells. Here, we further demonstrated that KLF4, a key pluripotency factor, is a direct transcriptional target of Nrf2 in arsenic-exposed human bronchial epithelial cells. ChIP-seq analysis identified multiple Nrf2 binding peaks at the Klf4 gene locus, which overlap with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout reduced both KLF4 expression and enhancer marker enrichment, accompanied by a global decrease in KLF4 binding across the genome. In wild-type (WT) cells, arsenic treatment increased KLF4 binding on genes involved in oncogenic pathways such as STAT3, SOX2, Nrf2, cell growth, Hedgehog, and EMT. We also found that KLF4 engages in a self-feedback loop in response to Nrf2 signaling. Lastly, our data showed that the co-occupancy of Nrf2 and KLF4 is crucial for establishing active enhancer hubs in the genome. These findings suggest that Nrf2s oncogenic effects are, in part, mediated by Nrf2 dependent self-amplification of KLF4 expression and function. Thus, targeting both Nrf2 and KLF4 could be a promising therapeutic strategy for eliminating cancer stem-like cells.

cancer biology↗

bioRxiv2024

Myosin light chain 3 serves as a receptor for nervous necrosis virus entry into host cells via the macropinocytosis pathway

Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (Oryzias melastigma) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which dependents on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3s crucial role in NNV entry and its potential as an antiviral target.

microbiology↗

bioRxiv2024

mTOR variants activation discovers PI3K-like cryptic pocket, expanding allosteric, mutant-selective inhibitor designs

mTOR plays a crucial role in PI3K/AKT/mTOR signaling. We hypothesized that mTOR activation mechanisms driving oncogenesis can advise effective therapeutic designs. To test this, we combined cancer genomic analysis with extensive molecular dynamics simulations of mTOR oncogenic variants. We observed that conformational changes within mTOR kinase domain are associated with multiple mutational activation events. The mutations disturb the -packing formed by the kAL, k3, k9, k9b, and k10 helices in the kinase domain creating cryptic pocket. Its opening correlates with opening of the catalytic cleft, including active site residues realignment, favoring catalysis. The cryptic pocket created by disrupted -packing coincides with the allosteric pocket in PI3K can be harmoniously fitted by the PI3K allosteric inhibitor RLY-2608, suggesting that analogous drugs designed based on RLY-2608 can restore the packed -structure, resulting in mTOR inactive conformation. Our results exemplify that knowledge of detailed kinase activation mechanisms can inform innovative allosteric inhibitor development.

cancer biology↗

bioRxiv2024

Arginine methylation coordinates with phosphorylation to regulate NADP+ synthesis

NADK is the sole cytosolic enzyme responsible for synthesizing NADP+ from NAD+ within cells. The homeostasis of NAD+/NADP+ is controlled by NADK, usually dysregulated in various cancers, yet the precise underlying regulatory mechanisms remain largely unknown. In this study, we discover that PRMT6 methylates NADK at R39, R41, and R45, resulting in the suppression of NADK kinase activity and NADP+ synthesis. Mutations of these sites promote cancer cell proliferation and tumor growth. PRMT6-mediated methylation of NADK coordinates with Akt-mediated phosphorylation to regulate NADK, which stimulates its activity to increase NADP+ production through relief of an autoinhibitory function inherent to its amino terminus. PRMT6 also inhibits NADK activity in a phosphorylation-independent manner. Furthermore, NADK methylation is upregulated by RB1/E2F pathway in high-fat diet mice. Downregulation of NADK methylation in HCC enhances NADP+ production to promote cancer development. Our findings illuminate the molecular regulatory mechanisms governing NAD+/NADP+ homeostasis, suggesting that the PRMT6-NADK axis emerges as a direct player in high energy state. Furthermore, our research suggests potential therapeutic targets through chemical and genetic interventions. SignificancePrevious studies revealed that phosphorylation of NADK activates its activity in response to nutrient or other signaling pathways. Here, we discovered that PRMT6 methylates NADK at residues R39, R41, and R45, leading to the suppression of NADK kinase activity and NADP+ synthesis. This PRMT6-mediated methylation works in conjunction with Akt-mediated phosphorylation to regulate NADK. Additionally, we found that NADK methylation is upregulated by the RB1/E2F pathway in mice on a high-fat diet. In hepatocellular carcinoma (HCC), the downregulation of NADK methylation enhances NADP+ production, thereby promoting cancer development. Our findings provide a significant breakthrough in understanding the regulation of NADK and its response to environmental factors.

cancer biology↗

bioRxiv2024

Injectable Janus Base Nanomatrix (JBNm) in Maintaining Long-Term Homeostasis of Regenerated Cartilage for Tissue Chip Applications

Engineered cartilage tissues have wide applications in in vivo cartilage repair as well as in vitro models, such as cartilage-on-a-chip or cartilage tissue chips. Currently, most cartilage tissue engineering approaches focus on promoting chondrogenesis of stem cells to produce regenerated cartilage. However, this regenerated cartilage can dedifferentiate into fibrotic tissue or further differentiate into hypertrophic or calcified cartilage. One of the most challenging objectives in cartilage tissue engineering is to maintain long-term cartilage homeostasis. Since the microenvironment of engineered cartilage tissue is crucial for stem cell adhesion, proliferation, differentiation, and function, we aim to develop a novel scaffold that can maintain the long-term homeostasis of regenerated cartilage. Therefore, we developed a library of Janus base nanomatrices (JBNms), composed of DNA-inspired Janus nanotubes (JBNts) as well as cartilage extracellular matrix (ECM) proteins. The JBNms were developed to selectively promote chondro-lineage cell functions while inhibiting bone and endothelial cell growth. More importantly, the JBNm can effectively promote chondrogenesis while inhibiting hypertrophy, osteogenesis, angiogenesis, and dedifferentiation. Additionally, the JBNm is injectable, forming a solid scaffold suitable for producing and maintaining regenerated cartilage tissue in microfluidic chips, making it ideal for tissue chip applications. In this study, we successfully created cartilage tissue chips using JBNms. These chips can model cartilage tissue even after long-term culture and can also mimic arthritis progression, making them useful for drug screening. Thus, we have developed a novel nanomaterial approach for improved cartilage tissue engineering and cartilage tissue chip applications.

bioengineering↗

bioRxiv2024

JunB-HBZ nuclear translocation by TGF-beta is a key driver in HTLV-1-mediated leukemogenesis

The HTLV-1 bZIP factor (HBZ) gene, which is the only viral gene conserved and consistently expressed in all adult T-cell leukemia-lymphoma (ATL) cases, is critical for ATL oncogenesis. Although HBZ protein is found in both the nucleus and the cytoplasm, the dynamics of HBZ protein localization and its contribution to oncogenesis have not been fully elucidated. In this study, we analyzed the subcellular expression pattern of HBZ in primary HTLV-1-infected T cells from asymptomatic carriers and leukemic cells of ATL patients using the Proximity Ligation Assay. Nuclear localization of HBZ protein was significantly higher in fresh ATL cells than in HTLV-1-infected cells from carriers. Importantly, translocation of HBZ protein from the cytoplasm to the nucleus after TGF-{beta} activation was observed in ATL patients, but not in HTLV-1 carriers. In ATL cells, the cellular transcription factors JunB and pSmad3 interact with HBZ and facilitate its nuclear translocation upon TGF-{beta} stimulation. JUNB knockdown inhibits cell proliferation in vitro and in vivo and promotes apoptosis in ATL cells but not in HTLV-1-infected non-leukemic cells, indicating that JunB has important roles in maintaining ATL cells. In conclusion, TGF-{beta}-induced nuclear translocation of HBZ-JunB complexes is associated with ATL oncogenesis.

microbiology↗

bioRxiv2024

Patterns of extreme outlier RNA expression in population data reveal sporadic over-activation of genes with co-regulated modules in subsets of individuals

BackgroundMost RNA-Seq datasets harbor genes with extreme expression levels in some samples. Such extreme outliers are usually treated as technical errors and are removed from the data before further statistical analysis. Here we focus on the patterns of such outlier expression. ResultsOur study is based on multiple datasets, including outbred and inbred mice, humans from the GTEx dataset, different Drosophila species and single-nuclei sequencing experiments from human brain tissues. All show comparable general patterns of outlier expression. Different individuals can harbor very different numbers of outliers, with some individuals showing extreme numbers in only one out of several organs of the respective individual. A three-generation family analysis in mice was generated and analyzed for the inheritance of outlier patterns. We find that most extreme over-expressions are not inherited, i.e., appear to be sporadically generated in individuals. Still, co-regulated outlier expressions are identifiable in various gene groups, and some correspond with known pathways. Among the co-regulated genes with extreme outlier expression are also the hormone genes prolactin and growth hormone, both in mice and humans, for which we include also protein level data from human cohorts. ConclusionsWe show that outlier patterns of gene expression are a biological reality occurring universally across tissues and species. Most of the outlier expressions are spontaneous and not inherited. We discuss the possibility that the outlier patterns reflect edge of chaos effects that are expected for systems of non-linear interactions and feedback loops, such as gene regulatory networks.

genomics↗