Biology subjects

Qian, S.

Publications and source records attributed to Qian, S..

31 records · Page 2Linked to original sources

bioRxiv2022

Adjusting for genetic confounders in transcriptome-wide association studies leads to reliable detection of causal genes

Expression Quantitative Trait Loci (eQTLs), provide valuable information on the effects of genetic variants. Many methods have been developed to leverage eQTLs to nominate candidate genes of complex traits, including colocalization analysis, transcriptome-wide association studies (TWAS), and Mendelian Randomization (MR)-based methods. All these methods, however, suffer from a key problem: when using the eQTLs of a gene to assess its role in a trait, nearby variants and nearby genetic components of expression of other genes can be correlated with the eQTLs of the test gene, while affecting the trait directly. These "genetic confounders" often lead to false discoveries. We introduced a novel statistical framework to address this challenge. Our method, causal-TWAS (cTWAS), borrowed ideas from statistical fine-mapping, and allowed us to adjust all genetic confounders. In our simulations, we found that existing methods based on TWAS, colocalization or MR all suffered from high false positive rates, often greater than 50%. In contrast, cTWAS showed calibrated false positive rates while maintaining power. Application of cTWAS on several common traits highlighted the weakness of existing methods and discovered novel candidate genes. In conclusion, cTWAS is a novel statistical framework to integrate eQTL and GWAS data, enabling reliable gene discoveries.

genomics↗

bioRxiv2022

A Purinergic Mechanism Underlying Metformin Regulation of Hyperglycemia

Metformin, created in 1922, has been the first-line medication treating type 2 diabetes mellitus for almost 70 years; however, its mechanism of action has been heavily debated, partly because most prior studies used supratherapeutic concentrations exceeding 1mM. Here we report that at a clinically relevant concentration of 10 M, metformin blocks high glucose-stimulated ATP secretion from hepatocytes mediating its antihyperglycemic action. Following glucose administration, mice demonstrate increased circulating ATP concentrations, which are prevented by metformin. Extracellular ATP through P2Y2 receptors (P2Y2R) compromises insulin-induced AKT activation and increases hepatic glucose production. In addition, metformin-dependent improvement in glucose tolerance is abolished in P2Y2R-null mice. Thus, removing the target of extracellular ATP, P2Y2R, mimics the effects of metformin, revealing a novel purinergic antidiabetic mechanism for metformin. One-Sentence SummaryMetformin abolishes high glucose-stimulated ATP secretion, preventing purinergic mechanism-mediated hepatic insulin resistance and glucose production.

pharmacology and toxicology↗

bioRxiv2022

DENSS-Multiple: A Structure Reconstruction Method using Multiple Contrast Variation of Small-Angle Neutron Scattering Based on the DENSS Algorithm

Small-angle neutron scattering (SANS) provides easily manipulable neutron contrast variation that has been widely exploited to study the structure and function of biological macromolecules and their complex in solution. Here, we developed a method called DENSS-Multiple based on the DENSS (DENsity from Solution Scattering) algorithm to provide ab initio structure reconstruction with SANS contrast variation data. This new tool can exploit additional information in different SANS contrasts for improved ab initio reconstruction results.

biophysics↗

bioRxiv2021

The P2Y2 Nucleotide Receptor Mediates Monocyte Tissue Factor Expression and Endotoxemia Death in Mice

Recently we reported that in human coronary artery endothelial cells, activation of the P2Y2 receptor (P2Y2R) induces up-regulation of tissue factor (TF), a vital initiator of the coagulation cascade. However, others have shown that monocyte TF is more critical than endothelial TF in provoking a pro-thrombotic state. Thus, we aimed to study whether monocytes express the P2Y2R, its role in controlling TF expression, and its relevance in vivo. RT-PCR and receptor activity assays revealed that among the eight P2Y nucleotide receptors, the P2Y2 subtype was selectively and functionally expressed in human monocytic THP-1 cells and primary monocytes. Stimulation of the cells by ATP or UTP dramatically increased TF protein expression, which was abolished by AR-C118925, a selective P2Y2R antagonist, or by siRNA silencing the P2Y2R. In addition, UTP or ATP treatment induced a rapid accumulation of TF mRNA preceded with an increased TF pre-mRNA, indicating enhanced TF gene transcription. In addition, stimulation of the monocyte P2Y2R significantly activated ERK1/2, JNK, p38, and Akt, along with their downstream transcription factors including c-Jun, c-Fos, and ATF-2, whereas blocking these pathways respectively, all significantly suppressed P2Y2R-mediated TF expression. Furthermore, we found that LPS triggered ATP release and TF expression, the latter of which was suppressed by apyrase or P2Y2R blockage. Importantly, P2Y2R-null mice were more resistant than wild-type mice in response to a lethal dose of LPS, accompanied by much less TF expression in bone marrow cells. These findings demonstrate for the first time that the P2Y2R mediates TF expression in human monocytes through mechanisms involving ERK1/2, JNK, p38, and AKT, and that P2Y2R deletion protects the mice from endotoxemia-induced TF expression and death, highlighting monocyte P2Y2R may be a new drug target for the prevention and/or treatment of relevant thrombotic disease.

pharmacology and toxicology↗

bioRxiv2021

The genome of an apodid holothuroid (Chiridota heheva) provides insights into its adaptation to deep-sea reducing environment

Cold seeps and hydrothermal vents are deep-sea reducing environments that are characterized by a lack of oxygen, photosynthesis-derived nutrients and a high concentration of reducing chemicals. Apodida is an order of deep-sea echinoderms lacking tube feet and complex respiratory trees, which are commonly found in holothurians. Chiridota heheva Pawson & Vance, 2004 (Apodida: Chiridotidae) is one of the few echinoderms that resides in deep-sea reducing environments. Unlike most cold seep and hydrothermal vent-dwelling animals, C. heheva does not survive by maintaining an epi- or endosymbiotic relationship with chemosynthetic microorganisms. The species acquires nutrients by extracting organic components from sediment detritus and suspended material. Here, we report a high-quality genome of C. heheva as a genomic reference for echinoderm adaptation to reducing environments. Chiridota heheva likely colonized its current habitats in the early Miocene. The expansion of the aerolysin-like protein family in C. heheva compared with other echinoderms might be involved in the disintegration of microbes during digestion, which in turn facilitates the species adaptation to cold seep environments. Moreover, several hypoxia-related genes were subject to positive selection in the genome of C. heheva, which contributes to their adaptation to hypoxic environments.

genomics↗

bioRxiv2021

Cdc14 activates autophagy to regulate spindle pole body dynamics during meiosis

Autophagy, a conserved eukaryotic lysosomal degradation pathway that responds to environmental and cellular cues, is regulated by multiple signaling pathways that oversee cell survival, growth, and proliferation. In budding yeast, autophagy plays an essential role in meiotic exit, although the molecular mechanisms underlying its regulation and cargo selection remain unknown. In this study, we found that autophagy is maintained during meiosis and is upregulated at anaphase I and anaphase II. In addition, we found that cells with higher levels of autophagy during meiosis I and II completed meiosis faster, and that genetically activated autophagy machinery increased sporulation efficiency. Strikingly, our data revealed that Cdc14, a highly conserved phosphatase that counteracts Cdc28 (CDK1), is a meiosis-specific autophagy regulator. At anaphase I and anaphase II, Cdc14 was activated and released from the nucleolus into the cytoplasm, where it dephosphorylated Atg13 to stimulate Atg1 kinase activity and thus autophagy. Importantly, the meiosis-specific spindle pole body (SPB, the yeast centrosome) component (Spo74) was sensitized to autophagy-mediated degradation at anaphase II, upon its dephosphorylation by Cdc14. Together, our findings reveal a meiosis-tailored mechanism of Cdc14 that spatiotemporally guides meiotic autophagy activity to control SPB dynamics.

cell biology↗

bioRxiv2021

Predicting Epigenomic Functions of Genetic Variants in the Context of Neurodevelopment via Deep Transfer Learning

Decoding the regulatory effects of non-coding variants is a key challenge in understanding the mechanisms of gene regulation as well as the genetics of common diseases. Recently, deep learning models have been introduced to predict genome-wide epigenomic profiles and effects of DNA variants, in various cellular contexts, but they were often trained in cell lines or bulk tissues that may not be related to phenotypes of interest. This is particularly a challenge for neuropsychiatric disorders, since the most relevant cell and tissue types are often missing in the training data of such models. To address this issue, we introduce a deep transfer learning framework termed MetaChrom that takes advantage of both a reference dataset - an extensive compendium of publicly available epigenomic data, and epigenomic profiles of cell types related to specific phenotypes of interest. We trained and evaluated our model on a comprehensive set of epigenomic profiles from fetal and adult brain, and cellular models representing early neurodevelopment. MetaChrom predicts these epigenomic features with much higher accuracy than previous methods, and than models without the use of reference epigenomic data for transfer learning. Using experimentally determined regulatory variants from iPS cell-derived neurons, we show that MetaChrom predicts functional variants more accurately than existing non-coding variant scoring tools. By combining genome-wide association study (GWAS) data with MetaChrom predictions, we prioritized 31 SNPs for Schizophrenia (SCZ). These candidate SNPs suggest potential risk genes of SCZ and the biological contexts where they act. In summary, MetaChrom is a general transfer learning framework that can be applied to the study of regulatory functions of DNA sequences and variants in any disease-related cell or tissue types. The software tool is available at https://github.com/bl-2633/MetaChrom and a prediction web server is accessible at https://metachrom.ttic.edu/.

bioinformatics↗

bioRxiv2020

Super-dosed butyrate induces a revisable metabolic paralysis through transient mitochondrial reprogramming in the gut-brain axis

Background and purposeSodium butyrate (SB) is a major product of gut microbiota with signaling activity in the human body. However, the toxic effect of SB remains largely unknown. This issue is addressed in current study. Experimental approachSB (0.3 - 2.5 g/kg) was administrated through a single peritoneal injection in mice. The core body temperature and mitochondrial function in the brain hypothalamus were monitored. Pharmacodynamics, targeted metabolomics, electron microscope, oxygen consumption rate and gene knockdown were employed to dissect the mechanism for the toxic effect. Key resultsThe temperature was reduced by SB (1.2 -2.5 g/kg) in a dose-dependent manner in mice for 2-4 hr. In the brain, the effect was associated with SB elevation and neurotransmitter (Glutamate and GABA) reduction. The mitochondria exhibited a transient volume expansion and crista loss in the hypothalamic neurons. ADP/ATP ratio was increased with accumulation of intermediate metabolites in the glycolysis, TCA cycle and pentose phosphate pathways. The mitochondrial protein, adenine nucleotide transporter (ANT), was activated for proton transportation leading to a transient potential collapse by proton leak. The SB activity was attenuated by ANT inhibition from gene knockdown or pharmacological blocker. The temperature drop was attenuated by i.p. injection of norepinephrine. The HDAC inhibitors, such as SAHA and pyruvate, did not exhibit the same effect. Conclusion and implicationsSuper-dosed SB generated an immediate and reversible toxic effect for inhibition of body temperature through transient mitochondrial reprogramming in the brain. The mechanism was quick activation of ANT proteins for the proton leak in mitochondria.

pharmacology and toxicology↗

bioRxiv2020

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

The new coronavirus (2019-nCoV) outbreak from December 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by 2019-nCov to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, especially in the lung. 2019-nCoV may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted "CellPhoneDB" analysis to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.

immunology↗

bioRxiv2019

Robust Neural Networks are More Interpretable for Genomics

Deep neural networks (DNNs) have been applied to a variety of regulatory genomics tasks. For interpretability, attribution methods are employed to provide importance scores for each nucleotide in a given sequence. However, even with state-of-the-art DNNs, there is no guarantee that these methods can recover interpretable, biological representations. Here we perform systematic experiments on synthetic genomic data to raise awareness of this issue. We find that deeper networks have better generalization performance, but attribution methods recover less interpretable representations. Then, we show training methods promoting robustness - including regularization, injecting random noise into the data, and adversarial training - significantly improve interpretability of DNNs, especially for smaller datasets.

genomics↗

bioRxiv2019

Leveraging genetic interaction for adverse drug-drug interaction prediction

In light of increased co-prescription of multiple drugs, the ability to discern and predict drug-drug interactions (DDI) has become crucial to guarantee the safety of patients undergoing treatment with multiple drugs. However, information on DDI profiles is incomplete and the experimental determination of DDIs is labor-intensive and time-consuming. Although previous studies have explored various feature spaces for in silico screening of interacting drug pairs, no method currently provides reliable predictions outside of their training sets. Here we demonstrate for the first time targets of adversely interacting drug pairs are significantly more likely to have synergistic genetic interactions than non-interacting drug pairs. Leveraging genetic interaction features and a novel training scheme, we construct a gradient boosting-based classifier that achieves robust DDI prediction even for drugs whose interaction profiles are completely unseen during training. We demonstrate that in addition to classification power--including the prediction of 432 novel DDIs--our genetic interaction approach offers interpretability by providing plausible mechanistic insights into the mode of action of DDIs.

bioinformatics↗

bioRxiv2018

Effective principal components analysis of SNP data

PCA is frequently used to display and discover patterns in SNP data from humans, animals, plants, and microbes--especially to elucidate population structure. Given the popularity of PCA, one might expect that PCA is understood well and applied effectively. However, our literature survey of 125 representative articles that apply PCA to SNP data shows that three choices have usually been made poorly: SNP coding, PCA variant, and PCA graph. Accordingly, we offer several simple recommendations for effective PCA analysis of SNP data. The ultimate benefit from informed and optimal choices of SNP coding, PCA variant, and PCA graph is expected to be discovery of more biology, and thereby acceleration of medical, agricultural, and other vital applications.

genomics↗

bioRxiv2018

Chicken uric acid elimination via the uric acid transporters BCRP and MRP4 in the liver, kidneys, and intestines

Breast cancer resistance protein (BCRP) and multidrug resistance protein 4 (MRP4) are involved in uric acid excretion in humans and mice. Despite evidence suggesting that chicken renal proximal tubular epithelial cells participate in uric acid secretion, the roles of BCRP and MRP4 in chickens remain unclear. This study evaluated the relationship between chicken BCRP and MRP4 expression and renal function in the liver, kidneys, and intestines. Sixty 20-day-old Isa brown laying hens were randomly divided into four groups: a control group (NC) and groups provided with sulfonamide-treated drinking water (SD), a diet supplemented with fishmeal (FM), and an intraperitoneal injection of uric acid (IU). Serum uric acid, creatinine, and blood urea nitrogen (BUN) levels were significantly higher in the SD and IU groups than in the NC group. BCRP and MRP4 levels in the SD and IU groups were significantly increased in the kidneys and ileum and decreased in the liver. In the FM group, BCRP and MRP4 were significantly increased in the kidneys and slightly increased in the ileum. These results demonstrate that chicken BCRP and MRP4 are involved in renal and intestinal uric acid excretion. When renal function is impaired, serum uric acid increased and BCRP and MRP4 in the liver, kidneys, and ileum exhibit compensatory increases; when renal function is normal, serum uric acid changes have no effect on ileum BCRP and MRP4 expression. Therefore, this study may provide the references to the uric acid regulation in human.

physiology↗