Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 505 records · Page 28Linked to original sources

bioRxiv2023

Cis- and trans-eQTL TWAS of breast and ovarian cancer identify more than 100 risk associated genes in the BCAC and OCAC consortia

Transcriptome-wide association studies (TWAS) have investigated the role of genetically regulated transcriptional activity in the etiologies of breast and ovarian cancer. However, methods performed to date have only considered regulatory effects of risk associated SNPs thought to act in cis on a nearby target gene. With growing evidence for distal (trans) regulatory effects of variants on gene expression, we performed TWAS of breast and ovarian cancer using a Bayesian genome-wide TWAS method (BGW-TWAS) that considers effects of both cis- and trans-expression quantitative trait loci (eQTLs). We applied BGW-TWAS to whole genome and RNA sequencing data in breast and ovarian tissues from the Genotype-Tissue Expression project to train expression imputation models. We applied these models to large-scale GWAS summary statistic data from the Breast Cancer and Ovarian Cancer Association Consortia to identify genes associated with risk of overall breast cancer, non-mucinous epithelial ovarian cancer, and 10 cancer subtypes. We identified 101 genes significantly associated with risk with breast cancer phenotypes and 8 with ovarian phenotypes. These loci include established risk genes and several novel candidate risk loci, such as ACAP3, whose associations are predominantly driven by trans-eQTLs. We replicated several associations using summary statistics from an independent GWAS of these cancer phenotypes. We further used genotype and expression data in normal and tumor breast tissue from the Cancer Genome Atlas to examine the performance of our trained expression imputation models. This work represents a first look into the role of trans-eQTLs in the complex molecular mechanisms underlying these diseases.

genetics↗

bioRxiv2023

Sensory-memory interactions via modular structure explain errors in visual working memory

Errors in stimulus estimation reveal how stimulus representation changes during cognitive processes. Repulsive bias and minimum variance observed near cardinal axes are well-known error patterns typically associated with visual orientation perception. Recent experiments suggest that these errors continuously evolve during working memory, posing a challenge that neither static sensory models nor traditional memory models can address. Here, we demonstrate that these evolving errors, maintaining characteristic shapes, require network interaction between two distinct modules. Each module fulfills efficient sensory encoding and memory maintenance, which cannot be achieved simultaneously in a single-module network. The sensory module exhibits heterogeneous tuning with strong inhibitory modulation reflecting natural orientation statistics. While the memory module, operating alone, supports homogeneous representation via continuous attractor dynamics, the fully connected network forms discrete attractors with moderate drift speed and nonuniform diffusion processes. Together, our work underscores the significance of sensory-memory interaction in continuously shaping stimulus representation during working memory.

neuroscience↗

bioRxiv2023

Urine proteomic analysis of patients with schizophrenia

We tried to explore the difference of urinary proteome between unmedicated schizophrenia patients and normal people through a small number of cases. The results showed that a total of 35 differential proteins were screened in the schizophrenia group compared with the healthy control group. Through random grouping evaluation, it has 91.4 % credibility. Fifteen of the differentially expressed proteins were reported to be related to schizophrenia mechanism, drug target or nervous system regulation. Among them, the aromatic amino acid decarboxylase related to the pathogenesis of schizophrenia can distinguish all 10 patients and 9 normal people with 100 % accuracy in this study, and the AUC value of 17 proteins is greater than or equal to 0.9. The biological pathways enriched by differentially expressed proteins include ephrin receptor signaling pathway, positive regulation of long-term potentiation (LTP), etc. This study shows that urine proteomics can reflect the difference between schizophrenia and healthy controls, and has the potential as a diagnostic marker.

biochemistry↗

bioRxiv2023

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1

Despite the unique ability of pioneer transcription factors (PFs) to target nucleosomal sites in closed chromatin, they only bind a small fraction of their genomic motifs. The underlying mechanism of this selectivity is not well understood. Here, we design a high-throughput assay called ChIP-ISO to systematically dissect sequence features affecting the binding specificity of a classic PF, FOXA1. Combining ChIP-ISO with in vitro and neural network analyses, we find that 1) FOXA1 binding is strongly affected by co-binding TFs AP-1 and CEBPB, 2) FOXA1 and AP-1 show binding cooperativity in vitro, 3) FOXA1s binding is determined more by local sequences than chromatin context, including eu-/heterochromatin, and 4) AP-1 is partially responsible for differential binding of FOXA1 in different cell types. Our study presents a framework for elucidating genetic rules underlying PF binding specificity and reveals a mechanism for context-specific regulation of its binding.

genetics↗

bioRxiv2023

Deletion of sulfate transporter SUL1 extends yeast replicative lifespan via reduced PKA signaling instead of decreased sulfate uptake

The regulation of cellular metabolism and growth in response to nutrient availability is crucial for cell survival and can significantly impact on lifespan. Central to this regulation is a class of transporters that sense and transport specific nutrients and transduce the signal downstream to control genes responsible for growth and survival. In this study, we identified SUL1, a plasma membrane transporter responsible for regulating the entry of extracellular sulfate in Saccharomyces cerevisiae, as a key gene for regulating lifespan. We conducted a systematic analysis to delineate the downstream mechanism underlying the lifespan extension by SUL1 deletion. Surprisingly, we found that the lifespan extending effect of SUL1 deletion is not due to decreased sulfate transport. The SUL1 deletion mutant exhibited decreased PKA signaling, resulting in a series of downstream effects, including increased stress-protective trehalose and glycogen, increased nuclear translocation of MSN2, elevated expression of general stress response genes, enhanced autophagy, and reduced expression of amino acid biosynthetic and ribosomal genes. We demonstrated that the observed increase in lifespan is dependent on MSN2 and autophagy pathways. Our findings exemplify the influence of nutrient signaling rather than the nutrient itself on lifespan regulation and further substantiate the pivotal role of the PKA pathway in this process.

molecular biology↗

bioRxiv2023

Poisoning medical knowledge using large language models

Biomedical knowledge graphs constructed from scientific literature have been widely used to validate biological discoveries and generate new hypotheses. Recently, large language models (LLMs) have demonstrated a strong ability to generate human-like text data. While most of these text data have been useful, LLM might also be used to generate malicious content. Here, we investigate whether it is possible that a malicious actor can use LLM to generate a malicious paper that poisons scientific knowledge graphs and further affects downstream biological applications. As a proof-of-concept, we develop Scorpius, a conditional text generation model that generates a malicious paper abstract conditioned on a promoting drug and a target disease. The goal is to fool the knowledge graph constructed from a mixture of this malicious abstract and millions of real papers so that knowledge graph consumers will misidentify this promoting drug as relevant to the target disease. We evaluated Scorpius on a knowledge graph constructed from 3,818,528 papers and found that Scorpius can increase the relevance of 71.3% drug disease pairs from the top 1000 to the top 10 by only adding one malicious abstract. Moreover, the generation of Scorpius achieves better perplexity than ChatGPT, suggesting that such malicious abstracts cannot be efficiently detected by humans. Collectively, Scorpius demonstrates the possibility of poisoning scientific knowledge graphs and manipulating downstream applications using LLMs, indicating the importance of accountable and trustworthy scientific knowledge discovery in the era of LLM.

bioinformatics↗

bioRxiv2023

A high-performance brain-sentence communication designed for logosyllabic language

Many severe neurological diseases, such as stroke and amyotrophic lateral sclerosis, can impair or destroy the ability of verbal communication. Recent advances in brain-computer interfaces (BCIs) have shown promise in restoring communication by decoding neural signals related to speech or motor activities into text. Existing research on speech neuroprosthesis has predominantly focused on alphabetic languages, leaving a significant gap of logosyllabic languages such as Mandarin Chinese which are spoken by more than 15% of the world population. Logosyllabic languages pose unique challenges to brain-to-text decoding due to extended character sets (e.g., 50,000+ for Mandarin Chinese) and complex mapping between characters and pronunciation. To address these challenges, we established a speech BCI designed for Mandarin, decoding speech-related stereoelectroencephalography (sEEG) signals into coherent sentences. We leverage the unique acoustic features of Mandarin Chinese syllables, constructing prediction models for syllable components (initials, tones, and finals), and employ a language model to resolve pronunciation to character ambiguities according to the semantic context. This method leads to a high-performance decoder with a median character accuracy of 71.00% over the full character set, demonstrating huge potentials for clinical application. To our knowledge, we are the first to report brain-to-sentence decoding for logosyllabic languages over full character set with a large intracranial electroencephalography dataset.

neuroscience↗

bioRxiv2023

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.

cancer biology↗

bioRxiv2023

Ggnbp2 regulates synaptic development and autophagy in motor neurons

AbstractGenome-wide association studies (GWAS) have identified numerous candidate ALS risk variants, but their cellular functions are often unknown. Recent studies have identified a variant of GGNBP2 that results in increased expression. To better understand how this gene might contribute to disease, we investigated the function of Drosophila Ggnbp2 (dGgnbp2) in motor neurons. Loss of function studies showed that dGgnbp2 is required for motor neuron synaptic development. A human transgene completely rescued these phenotypes indicating that the gene is functionally conserved between humans and flies. Overexpression of dGgnbp2 caused severe locomotor defects in adult flies, consistent with ALS pathology. At the cellular level, dGgnbp2 regulated autophagy, a process commonly defective in ALS. Both overexpression and removal of dGgnbp2 reduced levels of the phosphorylated lipid, PI(3)P, an essential component of autophagosomes. Our study provides strong evidence that Ggnbp2 functions in motor neurons to regulate a cellular process commonly defective in ALS. TeaserThis study investigated the function of the ALS risk variant GGNBP2, in flies, and showed that it regulates autophagy in motor neurons.

neuroscience↗

bioRxiv2023

Berberine impairs spermatogenesis in mice by modulating ornithine metabolism via gut microbiota regulation

Berberine (BBR) is used to treat diarrhea clinically, its reproductive toxicity, however, is poorly documented. This study aims to investigate the impact of BBR on the male reproductive system. Gradient doses of BBR were administered orally to experimental mice for consecutive 14 days. The gut microbiota, sperm concentration of cauda epididymis, and serum testosterone levels were measured after the last dose for assessing the effects of BBR. Moreover, the metabolome and transcriptome of the mice and microbiota were also investigated. Intragastric BBR administration resulted in a significant decrease in serum testosterone levels and epididymal sperm concentration in mice, which was attributed to a dramatic decrease of Muribaculaceae abundance in the gut microbiota of mice. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment experiments also demonstrated that Muribaculaceae is necessary for spermatogenesis. Metabolomic analysis revealed that BBR affected the arginine and proline metabolism pathways, of which ornithine levels were downregulated after BBR administration. Intragastric administration of M.intestinale and its metabolite ornithine to BBR-treated mice achieved a recovery of sperm concentration and testosterone levels. RNA sequencing of testes showed the genes related to the LDLR-mediated cholesterol-synthesis testosterone pathway were downregulated after BBR administration. The levels of testosterone increased and Ldlr gene became more transcriptionally active in TM3 cells cultured in media supplemented with ornithine. This study for the first time revealed an association between BBR-induced gut Muribaculaceae dysbiosis and defects in spermatogenesis via ornithine metabolism, which provided a candidate and strategy for the treatment of infertility caused by a decreased serum testosterone level-induced by gut microbiota dysbiosis.

pharmacology and toxicology↗

bioRxiv2023

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we used sheep as an animal model for plain-to-plateau transplantation. We generated multi-omics data including time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterized transcriptional changes of all genes in each tissue, and examined multi-tissue temporal dynamics and transcriptional interactions among genes. In particular, we identified critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identified TAD-constrained cis-regulatory elements, which suppressed the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicated that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provided time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

genetics↗

bioRxiv2023

A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer

BACKGROUND & AIMSPDAC is characterized by significant matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, it is not clear the connection between matrix stiffness and the Warburg effect and the mechanisms of action in tumor progression. METHODSThe relationship between matrix stiffness and the Warburg effect was investigated from clinical, cellular, and bioinformatical perspectives. The ChIP and luciferase reporter gene assays were used to clarify the regulation mechanism of matrix stiffness on the expression of CLIC1. The expression profile and clinical significance of CLIC1 were determined in GEO datasets and a TMA. Loss-of-function and gain-of-function technics were used to determine the in vitro and in vivo functions of CLIC1. GSEA and western blotting revealed the underlying molecular mechanisms. RESULTSPDAC matrix stiffness is closely associated with the Warburg effect, and CLIC1 is a key molecule connecting tumor matrix stiffness and the Warburg effect. Increased CLIC1 expression induced by matrix stiffness correlates with poor prognosis in PDAC. CLIC1 acts as a promoter of glycolytic metabolism and facilitates tumor growth in a glycolysis-dependent manner. Mechanistically, CLIC1 inhibits the hydroxylation of HIF1 via ROS, which then increases the stability of HIF1. Collectively, PDAC cells can sense extracellular matrix stiffness and upregulate the expression of CLIC1, which facilitates the Warburg effect through ROS/HIF1 signaling, thereby supporting tumor growth. CONCLUSIONSIn the context of tumor therapy, targeted approaches can be considered from the perspectives of both extracellular matrix stiffness and tumor metabolism, of which CLIC1 is one of the targets.

cancer biology↗

bioRxiv2023

Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse

Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). EtOH is the most abused substance worldwide with chronic consumption often leading to the development of dependence and abuse. Unfortunately, the neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6fl/fl; DAT-iCreER mice to determine the role of RGS6 in VTA DA neurons on EtOH consumption and reward behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse VTA, and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in VTA DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6-/- mice. Strikingly, RGS6 loss from VTA DA neurons before or after EtOH behavioral reward is established significantly reduced ([~]50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies illuminate a critical role of RGS6 in the mesolimbic circuit in promoting EtOH seeking, reward, and reinstatement. We propose that RGS6 functions to promote DA transmission through its function as a negative modulator of GPCR-Gi/o-DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.

neuroscience↗

bioRxiv2023

A mechanical circuit in End4p coordinates force transmission during clathrin-mediated endocytosis

Mechanical forces are transmitted from the actin cytoskeleton to the membrane during clathrin-mediated endocytosis (CME) in the fission yeast Schizosaccharomyces pombe. The onset and termination of force transmission is tightly regulated temporally during different stages of CME, and spatially over the surface of the invaginated membrane. How force transmission is regulated and coordinated at the molecular scale is unclear. An adaptor protein in CME, End4p, directly transmits force by binding to both the membrane (through ANTH domain) and F-actin (through THATCH domain). We show that 8pN is required for stable binding between THATCH and F-actin. We also report the discovery and characterization of a new domain on End4p, which we named Rend (R domain in End4p), that resembles R12 of talin. Membrane localization of Rend primes the binding of THATCH to F-actin, and force-induced unfolding of Rend at 15pN terminates the transmission of force during CME. We show that the mechanical properties (mechanical stability, unfolding length, hysteresis) of Rend and THATCH are tuned to form an auto-regulated circuit for the initiation, transmission and termination of force between the actin cytoskeleton and membrane. Shorting the circuit leads to permanent End4p association with the membrane or with F-actin, or failure to enter the force transmission cycle. Mathematical modeling of force transmission through Rend-THATCH connection shows that input force from F-actin is buffered to a narrow range towards the membrane. The mechanical circuit by Rend and THATCH may be conserved and coopted evolutionarily in cell adhesion complexes.

cell biology↗

bioRxiv2023

SEM: sized-based expectation maximization for characterizing nucleosome positions and subtypes

Genome-wide nucleosome profiles are predominantly characterized using MNase-seq, which involves extensive MNase digestion and size selection to enrich for mono-nucleosome-sized fragments. Most available MNase-seq analysis packages assume that nucleosomes uniformly protect 147bp DNA fragments. However, some nucleosomes with atypical histone or chemical compositions protect shorter lengths of DNA. The rigid assumptions imposed by current nucleosome analysis packages ignore variation in nucleosome lengths, potentially blinding investigators to regulatory roles played by atypical nucleosomes. To enable the characterization of different nucleosome types from MNase-seq data, we introduce the Size-based Expectation Maximization (SEM) nucleosome calling package. SEM employs a hierarchical Gaussian mixture model to estimate the positions and subtype identity of nucleosomes from MNase-seq fragments. Nucleosome subtypes are automatically identified based on the distribution of protected DNA fragment lengths at nucleosome positions. Benchmark analysis indicates that SEM is on par with existing packages in terms of standard nucleosome-calling accuracy metrics, while uniquely providing the ability to characterize nucleosome subtype identities. Using SEM on a low-dose MNase H2B MNase-ChIP-seq dataset from mouse embryonic stem cells, we identified three nucleosome types: short-fragment nucleosomes, canonical nucleosomes, and dinucleosomes. The short-fragment nucleosomes can be divided further into two subtypes based on their chromatin accessibility. Interestingly, the subset of short-fragment nucleosomes in accessible regions exhibit high MNase sensitivity and display distribution patterns around transcription start sites (TSSs) and CTCF peaks, similar to the previously reported "fragile nucleosomes". These SEM-defined accessible short-fragment nucleosomes are found not just in promoters, but also in enhancers and other regulatory regions. Additional investigations reveal their co-localization with the chromatin remodelers Chd6, Chd8, and Ep400. In summary, SEM provides an effective platform for distinguishing various nucleosome subtypes, paving the way for future exploration of non-standard nucleosomes.

bioinformatics↗

bioRxiv2023

De novo generation of T-cell receptors with desired epitope-binding property by leveraging a pre-trained large language model

Generating T-cell receptors (TCRs) with desired epitope-binding properties is a fundamental step in the development of immunotherapies, yet heavily relies on laborious and expensive wet experiments. Recent advancements in generative artificial intelligence have demonstrated promising power in protein design and engineering. In this regard, we propose a large language model, termed Epitope-Receptor-Transformer (ERTransformer), for the de novo generation of TCRs with the desired epitope-binding property. ERTransformer is built on EpitopeBERT and ReceptorBERT, which are trained using 1.9 million epitope sequences and 33.1 million TCR sequences, respectively. To demonstrate the model capability, we generate 1000 TCRs for each of the five epitopes with known natural TCRs. The artificial TCRs exhibit low sequence identity (average Bit-score 27.64 with a standard deviation of 1.50) but high biological function similarity (average BLOSUM62 score 32.32 with a standard deviation of 12.01) to natural TCRs. Furthermore, the artificial TCRs are not very structurally identical to natural ones (average RMSD 2.84 [A] with a standard deviation of 1.21 [A]) but exhibit a comparable binding affinity towards the corresponding epitopes. Our work highlights the tremendous potential of applying ERTransformer to generate novel TCRs with desired epitope-binding ability.

bioinformatics↗

bioRxiv2023

Alasemenia, the earliest ovule with three wings and without cupule

The ovules or seeds (fertilized ovules) with wings are widespread and especially important for wind dispersal. However, the earliest ovules in the Famennian of the Late Devonian are rarely known about the dispersal syndrome and usually surrounded by a cupule. From Xinhang, Anhui, China, we report a new taxon of Famennian ovules, Alasemenia tria gen. et sp. nov. Each ovule possesses three integumentary wings evidently extending outwards, folding inwards along abaxial side and enclosing most part of nucellus. The ovule is borne terminally on smooth dichotomous branches and lacks a cupule. Alasemenia suggests that the integuments of the earliest ovules without a cupule evolved functions in wind dispersal and probable photosynthetic nutrition. It indicates that the seed wing originated earlier than other wind dispersal mechanisms such as seed plume and pappus, and that three- or four-winged seeds were followed by seeds with less wings. Mathematical analysis shows that three-winged seeds are more adapted to wind dispersal than seeds with one, two or four wings under the same condition.

paleontology↗

bioRxiv2023

Unlocking cellular plasticity: Enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation

The transformation of fibroblasts into epithelial cells is critical for iPSC reprogramming. In this report, we describe studies with PFI-3, a small molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunit of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings revealed that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition (MET) during iPSC formation. This transition was characterized by the upregulation of E-cadherin expression, a key protein involved in epithelial cell adhesion. Additionally, we identified COL11A1 as a reprogramming barrier and demonstrated COL11A1 knockdown increased reprogramming efficiency. Notably, we found that PFI-3 significantly reduced the expression of numerous extracellular matrix (ECM) genes, particularly those involved in collagen assembly. Our research provides key insights into the early stages of iPSC reprogramming, highlighting the crucial role of ECM changes and cellular plasticity in this process.

cell biology↗