Biology subjects

Cui, Q.

Publications and source records attributed to Cui, Q..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Defining the single base importance of human mRNAs and lncRNAs

As the fundamental unit of a gene and its transcripts, nucleotides have enormous impacts on molecular function and evolution, and thus on phenotypes and diseases. Given that different nucleotides on one gene often exhibit diverse levels of effects, it is quite crucial to comprehensively and quantitatively measure the importance of each base on a gene transcript, however, tools are still not available. Here we proposed Base Importance Calculator (BIC), an algorithm to calculate the importance score of single bases based on sequence information of human mRNAs and long noncoding RNAs (lncRNAs). We then confirmed its power by applying BIC to three different tasks. Firstly, we revealed that BIC can effectively evaluate the pathogenicity of both genes and single bases by analyzing the BIC scores and the pathogenicity of single nucleotide variations (SNVs). Moreover, the BIC score in the Cancer Genome Atlas (TCGA) somatic mutations is able to predict the prognosis of some cancers. Finally, we show that BIC can also precisely predict the transmissibility of SARS-CoV-2. The above results indicate that BIC is a useful tool for evaluating the single base important of human mRNAs and lncRNAs. Key PointsO_LIBIC could measure the single base importance of human mRNAs and lncRNAs. C_LIO_LIBIC could be applied to many aspects including measuring the pathogenicity of SNVs and enhancing the ability of predicting cancer survival. C_LIO_LIBIC could predict the transmissibility of SARS-CoV-2 C_LI

bioinformatics↗

bioRxiv2023

Integrin beta4 promotes DNA damage drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/Rac1

Anti-tumor drug resistance is a challenge for human triple-negative breast cancer treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote triple-negative breast cancer cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin {beta}4. Integrin {beta}4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in triple-negative breast cancer. These results indicate that the Integrin {beta}4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in triple-negative breast cancer.

cancer biology↗

bioRxiv2023

Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56 delta holoenzyme

An increasing number of mutations associated with devastating human diseases are diagnosed by whole-genome/exon sequencing. Recurrent de novo missense mutations have been discovered in B56{delta} (encoded by PPP2R5D), a regulatory subunit of protein phosphatase 2A (PP2A), that cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Single-particle cryo-EM structures show that the PP2A-B56{delta} holoenzyme possesses closed latent and open active forms. In the closed form, the long, disordered arms of B56{delta} termini fold against each other and the holoenzyme core, establishing dual autoinhibition of the phosphatase active site and the substrate-binding protein groove. The resulting interface spans over 190 [A] and harbors unfavorable contacts, activation phosphorylation sites, and nearly all residues with ID-associated mutations. Our studies suggest that this dynamic interface is close to an allosteric network responsive to activation phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations perturb the activation phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the wild variant.

biochemistry↗

bioRxiv2023

The IRE1α-endonuclease regulates PD-1 expression through a novel XBP1/miRNA-34a axis within Natural Killer cells

Activation of the IRE1-endonuclease is critical for Natural Killer (NK)-cell function. We describe a novel regulatory role for IRE1-endonuclease in fine-tuning NK-cell effector functions through an inter-connected activation of the transcription factor XBP1s and inhibition of microRNA-34a-5p (miR-34a-5p) to modulate PD-1 immune checkpoint expression. NK-cells, when exposed to cancer cells, activate IRE1-endonuclease mediated decay of miR-34a-5p. This reduces miR-34a-5p and consequently increases the expression of the target genes XBP1 and PD-1. IRE1-endonuclease activation not only enhances NK-cell effector function but also promotes PD-1 expression. PD-1 is itself directly regulated by miR-34a-5p, which binds to the 3UTR of PD-1 messenger RNA to repress PD-1 protein at the NK-cell surface. IRE1-pathway activation is impaired in the NK-cells of patients with Hodgkin Lymphoma, and miR-34a-5p and PD-1 expression are inversely correlated. The IRE1-pathway plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within NK-cells, that is disrupted in cancer patients.

cancer biology↗

bioRxiv2022

An alternative malonyl-CoA producing pathway in nature

Malonyl-CoA is a key metabolic intermediate for biosynthesis of diverse cellular molecules and natural products. Carboxylation of acetyl-CoA is almost the unique pathway for malonly-CoA biosynthesis. Biotechnological production of numerous value-added malonyl-CoA-derived chemicals require high intracellular supply of malonyl-CoA. However, because of the central role of acetyl-CoA in primary metabolism, it is difficult to develop flexible strategies to balance malonyl-CoA supply with other cellular metabolism. Here we find that there is a natural alternative malonyl-CoA-producing pathway, in which the key reaction is catalyzed by an -keto acid dehydrogenase complex BkdFGH from Streptomyces avermitilis. This dehydrogenase complex could efficiently catalyze biosynthesis of malonyl-CoA from oxaloacetate in addition to recognizing its native substrate branched-chain -keto acid. Oxaloacetate dehydrogenase (OADH) was shown to play important physiological roles during the regulation of biosynthesis of native malonyl-CoA-derived polyketides in Streptomyces. Furthermore, the oxlaocetate dehydrogenation reaction is thermodynamically superior to acetyl-CoA carboxylation and enable efficient bioproduction of diverse malonyl-CoA-derived chemicals in engineering Escherichia coli. This novel malonyl-CoA source thus has great potential in the biotechnological field.

microbiology↗

bioRxiv2022

Tunable image-mapping optical coherence tomography

We present tunable image-mapping optical coherence tomography (TIM-OCT), which can provide optimized imaging performance for a given application by using a programmable phase-only spatial light modulator in a low-coherence full-field spectral-domain interferometer. The resultant system can provide either a high lateral resolution or a high axial resolution in a snapshot without moving parts. Alternatively, the system can achieve a high resolution along all dimensions through a multiple-shot acquisition. We evaluated TIM-OCT in imaging both standard targets and biological samples. Additionally, we demonstrated the integration of TIM-OCT with computational adaptive optics in correcting sample-induced optical aberrations.

bioengineering↗

bioRxiv2022

Combating pancreatic cancer with ovarian cancer cells

With overall five-year survival rate less than 10%, pancreatic cancer (PC) represents the most lethal one in all human cancers. Given that the incidence of PC is still increasing and current cancer treatment strategies are often inefficacious, its therapy is still a huge challenge. Here, we first revealed ovarian serous carcinoma is mostly anti-correlated with pancreatic cancer in gene expression signatures. Based on this observation, we proposed that ovarian cancer cells could defense PC. To confirm this strategy, we first showed that ovarian cancer cell SKOV3 can significantly inhibit the proliferation of pancreatic cancer cell SW1990 when they were co-cultured. We further validated this strategy by an animal model of pancreatic cancer xenografts. The result showed that the injection of SKOV3 significantly inhibits pancreatic cancer xenografts. Moreover, we found that SKOV3 with transgenic African elephant TP53 gene further enhances the therapeutic effect. RNA-sequencing analysis revealed that the ovarian cancer cell treatment strikingly induced changes of genes being involved in pancreas function and phenotype (e.g. enhancing pancreas function, pancreas regeneration, and cell adhesion) but not immune and inflammation related functions, suggesting that the proposed strategy is different from immunotherapy and could be a novel strategy for cancer treatment.

cancer biology↗

bioRxiv2022

Animal complexity defines the functionality of synonymous mutations through mediating microRNA regulations

Most recently, Shen et al. revealed that most synonymous mutations (SMs) in yeast genes are strongly non-neutral, however, which was soon challenged by Kruglyak et al. who find no evidence for deleterious effect on fitness of SMs in yeast genes. We previously revealed that SMs in numerous human genes show functionality through changing miRNA regulations. Given that higher animals show higher complexity of miRNA regulations, here we present a hypothesis that SMs in lower animal genes show less functionality and vice versa. To confirm this, we comprehensively investigated the SMs changing miRNA regulations in yeast, C.elegans, Drosophila, mouse, and human. As expected, the result showed that the proportion of SMs affecting gene functionality through altering miRNA regulations is about 0%, 14%, 16%, 51%, and 60% in yeast, C. elegans, Drosophila, mouse, and human, respectively, suggesting that the complexity of animals indeed determines the functionality of SMs through mediating miRNA regulations. Finally, this study supports no evidence that most SMs in yeast genes are deleterious.

bioinformatics↗

bioRxiv2022

Membrane Obstacles Enhance the Sensitivity andSelectivity of Surface Condensation

Biomolecular phase separation has emerged as an essential mechanism for cellular organization. How cells respond to environmental stimuli in a robust and sensitive manner to build functional condensates at the proper time and location is only starting to be understood. Recently, lipid membranes have been recognized as an important regulatory center for biomolecular condensation. However, how the interplay between the phase behaviors of cellular membranes and surface biopolymers may contribute to the regulation of surface condensation remains to be elucidated. Using simulations and a mean-field theoretical model, we show that two key factors are the membranes tendency to phase separate and the surface polymers ability to reorganize local membrane composition. Surface condensate forms with high sensitivity and selectivity in response to features of biopolymer when positive co-operativity is established between coupled growth of the condensate and local lipid domains. This effect relating the degree of membrane-surface polymer co-operativity and condensate property regulation is shown to be robust by different ways of tuning the co-operativity, such as varying membrane protein obstacle concentration, lipid composition and the affinity between lipid and polymer. The general physical principle emerged from the current analysis may have implications in other biological processes and beyond.

biophysics↗

bioRxiv2022

Molecular mechanism of GTP binding- anddimerization-induced enhancement ofSar1-mediated membrane remodeling

The Sar1 GTPase initiates Coat Protein II (COPII)-mediated protein transport by generating membrane curvature at subdomains on the Endoplasmic Reticulum, where it is activated by the guanine nucleotide exchange factor (GEF) Sec12. Crystal structures of GDP- and GTP-bound forms of Sar1 suggest that it undergoes a conformational switch in which GTP binding enhances the exposure of an amino-terminal amphipathic helix necessary for efficient membrane penetration. However, key residues in the amino-terminus were not resolved in crystal structures, and experimental studies have suggested that the amino-terminus of Sar1 is solvent-exposed in the absence of membrane, even in the GDP-bound state. Therefore, the molecular mechanism by which GTP binding activates the membrane remodeling activity of Sar1 remains unclear. Using atomistic molecular dynamics simulations, we compare the membrane binding and curvature generation activities of Sar1 in its GDP- and GTP-bound states. We show that in the GTP-bound state, Sar1 inserts into the membrane with its complete (residues 1-23) amphipathic amino-terminal helix, while Sar1-GDP binds to the membrane only through its first 12 residues. Such differential membrane binding modes translate into significant differences in the protein volume inserted into the membrane. As a result, Sar1-GTP generates positive membrane curvature 10-20 times higher than Sar1-GDP. Dimerization of the GTP-bound form of Sar1 further amplifies curvature generation. Taken together, our results present a detailed molecular mechanism for how the nucleotide-bound state of Sar1 regulates its membrane binding and remodeling activities in a concentration dependent manner, paving the way toward a better understanding COPII-mediated membrane transport. Significance StatementAmphipathic helices play established roles in penetrating lipid bilayers to produce local membrane curvature. The degree of curvature generated has been suggested to depend on the penetration depth of the amphipathic helix, its amino acid sequence, and the protein volume inserted into the membrane. However, the relative contributions of each of these factors in membrane bending remain unclear. Using the Sar1 protein monomer bound to different nucleotides (GDP vs. GTP) and its GTP-bound dimeric form as examples, we explicitly show that while the precise amino acid sequence and insertion depth of the amphipathic helix are relevant, the generated membrane curvature is most correlated with the volume of protein insertion into the membrane.

biophysics↗

bioRxiv2022

Thermodynamic analysis of GASright dimerization supports a model in which stability is modulated by weak hydrogen bonding and van der Waals packing

The GASright motif, best known as the fold of the glycophorin A transmembrane dimer, is one of the most common dimerization motifs in membrane proteins, characterized by its hallmark GxxxG-like sequence motifs (GxxxG, AxxxG, GxxxS, and similar). Structurally, GASright displays a right-handed crossing angle and short inter-helical distance. Contact between the helical backbones favors the formation of networks of weak hydrogen bonds between C-H carbon donors and carbonyl acceptors on opposing helices (C-H***O=C). To understand the factors that modulate the stability of GASright, we previously presented a computational and experimental structure-based analysis of 26 predicted dimers. We found that the contributions of van der Waals packing and C-H hydrogen bonding to stability, as inferred from the structural models, correlated well with relative dimerization propensities estimated experimentally with the in vivo assay TOXCAT. Here we test this model with a quantitative thermodynamic analysis. We used FRET to determine the free energy of dimerization of a representative subset of 7 of the 26 original TOXCAT dimers using FRET. To overcome the technical issue arising from limited sampling of the dimerization isotherm, we introduced a globally fitting strategy across a set of constructs comprising a wide range of stabilities. This strategy yielded precise thermodynamic data that show strikingly good agreement between the original propensities and {Delta}G{degrees} of association in detergent, suggesting that TOXCAT is a thermodynamically driven process. From the correlation between TOXCAT and thermodynamic stability, the predicted free energy for all the 26 GASright dimers was calculated. These energies correlate with the in silico {Delta}E scores of dimerization that were computed on basis of their predicted structure. These findings corroborate our original model with quantitative thermodynamic evidence, strengthening the hypothesis that van der Waals and C-H hydrogen bond interactions are the key modulators of GASright stability. Secondary AbstractWe present a thermodynamic analysis of the dimerization of the GASright motif, a common dimerization motif in membrane proteins. Previously, we found that the stability of GASright is modulated by van der Waals packing and weak hydrogen bonds between C-H carbon donors and carbonyl acceptors on opposing helices. The experimental dimerization propensities were obtained with an in vivo assay. Here we assess this model quantitatively by measuring the free energy of dimerization of a subset of the original dimers. The thermodynamic data show strikingly good agreement between the original propensities and their {Delta}G{degrees} of association, confirming the model and strengthening the hypothesis that van der Waals and C-H hydrogen bond interactions are the key modulators of GASright stability.

biophysics↗

bioRxiv2022

Synaptotagmin 7 outperforms synaptotagmin 1 to open and stabilize nascent fusion pores via robust membrane penetration

Synaptotagmin-1 and synaptotagmin-7 are two prominent Ca2+ sensors that regulate exocytosis in neuronal and neuroendocrine cells. Upon binding Ca2+, both proteins partially penetrate lipid bilayers that bear anionic phospholipids, but the specific underlying mechanisms that enable them to trigger exocytosis remain controversial. Here, we examined the biophysical properties of these two synaptotagmin isoforms and compared their interactions with phospholipid membranes. We discovered that synaptotagmin-1*membrane interactions are greatly influenced by membrane order; tight packing of phosphatidylserine inhibits binding due to impaired membrane penetration. In contrast, synaptotagmin-7 exhibits robust membrane binding and penetration activity regardless of phospholipid acyl chain structure. Thus, synaptotagmin-7 is a "super-penetrator". We exploited these observations to specifically isolate and examine the role of membrane penetration in synaptotagmin function. Using nanodisc-black lipid membrane electrophysiology, we demonstrate that membrane penetration is a critical component that underlies how synaptotagmin proteins regulate reconstituted, exocytic fusion pores in response to Ca2+.

neuroscience↗

bioRxiv2022

Deep mutational scanning and machine learning reveal structural and molecular rules governing allosteric hotspots in homologous proteins

A fundamental question in protein science is where allosteric hotspots - residues critical for allosteric signaling - are located, and what properties differentiate them. We carried out deep mutational scanning (DMS) of four homologous bacterial allosteric transcription factors (aTF) to identify hotspots and built a machine learning model with this data to glean the structural and molecular properties of allosteric hotspots. We found hotspots to be distributed protein-wide rather than being restricted to "pathways" linking allosteric and active sites as is commonly assumed. Despite structural homology, the location of hotspots was not superimposable across the aTFs. However, common signatures emerged when comparing hotspots coincident with long-range interactions, suggesting that the allosteric mechanism is conserved among the homologs despite differences in molecular details. Machine learning with our large DMS datasets revealed that global structural and dynamic properties to be a strong predictor of whether a residue is a hotspot than local and physicochemical properties. Furthermore, a model trained on one protein can predict hotspots in a homolog. In summary, the overall allosteric mechanism is embedded in the structural fold of the aTF family, but the finer, molecular details are sequence-specific.

biochemistry↗

bioRxiv2022

Deciphering of Somatic Mutational Signatures of Cancer

Somatic mutational signatures (MSs) identified by genome sequencing play important roles in exploring the cause and development of cancer. Thus far, many such signatures have been identified, and some of them do imply causes of cancer. However, a major bottleneck is that we do not know the potential meanings (i.e., cancer causal or biological functions) and contributing genes for most of them. Here we presented a computational framework, Gene Somatic Genome Pattern (GSGP), which can decipher the molecular mechanisms of the MSs. More importantly, it is the first time, GSGP is able to process MSs from RNA sequencing, which greatly extended the applications of both MS analysis and RNA sequencing. As a result, GSGP analysis matches consistently with previous reports and identify the aetiologies for a number of novel signatures. Notably, we applied GSGP to RNA sequencing data and revealed an RNA-derived MS involved in deficient DNA mismatch repair (dMMR) and microsatellite instability (MSI) in colorectal cancer (CRC).

genomics↗

bioRxiv2021

Modeling of microRNA-derived disease network repurposes methotrexate for the prevention and therapy of abdominal aortic aneurysm in mice

Abdominal aortic aneurysm (AAA) is a highly lethal vascular disease characterized by permanent dilatation of the abdominal aorta. The main purpose of the current study is to search for noninvasive medical therapies for abdominal aortic aneurysm (AAA), for which there is currently no effective drug therapy. Network medicine represents a cutting-edge technology, as analysis and modeling of disease networks can provide critical clues regarding the etiology of specific diseases and which therapeutics may be effective. Here, we proposed a novel algorithm to quantify disease relations based on a large accumulated microRNA-disease association dataset and then built a disease network that covered 15 disease classes and included 304 diseases. Analysis revealed a number of patterns for these diseases; for example, diseases tended to be clustered and coherent in the network. Surprisingly, we found that AAA showed the strongest similarity with rheumatoid arthritis and systemic lupus erythematosus, both of which are autoimmune diseases, suggesting that AAA could be one type of autoimmune disease in etiology. Based on this observation, we further hypothesized that drugs for autoimmune disease could be repurposed for the prevention and therapy of AAA. Finally, animal experiments confirmed that methotrexate, a drug for autoimmune disease, was able to prevent the formation and inhibit the development of AAA.

bioinformatics↗

bioRxiv2021

B.1.1.529 escapes the majority of SARS-CoV-2 neutralizing antibodies of diverse epitopes

The SARS-CoV-2 B.1.1.529 variant (Omicron) contains 15 mutations on the receptor-binding domain (RBD). How Omicron would evade RBD neutralizing antibodies (NAbs) requires immediate investigation. Here, we used high-throughput yeast display screening1,2 to determine the RBD escaping mutation profiles for 247 human anti-RBD NAbs and showed that the NAbs could be unsupervised clustered into six epitope groups (A-F), which is highly concordant with knowledge-based structural classifications3-5. Strikingly, various single mutations of Omicron could impair NAbs of different epitope groups. Specifically, NAbs in Group A-D, whose epitope overlap with ACE2-binding motif, are largely escaped by K417N, G446S, E484A, and Q493R. Group E (S309 site)6 and F (CR3022 site)7 NAbs, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but still, a subset of NAbs are escaped by G339D, N440K, and S371L. Furthermore, Omicron pseudovirus neutralization showed that single mutation tolerating NAbs could also be escaped due to multiple synergetic mutations on their epitopes. In total, over 85% of the tested NAbs are escaped by Omicron. Regarding NAb drugs, the neutralization potency of LY-CoV016/LY-CoV555, REGN10933/REGN10987, AZD1061/AZD8895, and BRII-196 were greatly reduced by Omicron, while VIR-7831 and DXP-604 still function at reduced efficacy. Together, data suggest Omicron would cause significant humoral immune evasion, while NAbs targeting the sarbecovirus conserved region remain most effective. Our results offer instructions for developing NAb drugs and vaccines against Omicron and future variants.

immunology↗

bioRxiv2021

Communication determines population-level fitness under cation stress by modulating the ratio of motile to sessile B. subtilis cells

Bacterial populations frequently encounter potentially lethal environmental stress factors. Growing Bacillus subtilis populations are comprised of a mixture of "motile" and "sessile" cells but how this affects population-level fitness under stress is poorly understood. Here, we show that, unlike sessile cells, motile cells are readily killed by monovalent cations under conditions of nutrient deprivation - owing to elevated expression of the lytABC operon, which codes for a cell-wall lytic complex. Forced induction of the operon in sessile cells also causes lysis. We demonstrate that population composition is regulated by the quorum sensing regulator ComA, which can favor either the motile or the sessile state. Specifically social interactions by ComX-pheromone signaling enhance population-level fitness under stress. Our study highlights the importance of characterizing population composition and cellular properties for studies of bacterial physiology and functional genomics. Our findings open new perspectives for understanding the functions of autolysins and collective behaviors that are coordinated by chemical and electrical signals, with implications for multicellular development and biotechnology.

microbiology↗

bioRxiv2021

Toward comprehensive functional analysis of gene lists weighted by gene essentiality scores

Gene functional enrichment analysis represents one of the most popular bioinformatics methods for annotating the pathways and function categories of a given gene list. Current algorithms for enrichment computation such as Fishers exact test and hypergeometric test totally depend on the category count numbers of the gene list and one gene set. In this case, whatever the genes are, they were treated equally. However, actually genes show different scores in their essentiality in a gene list and in a gene set. It is thus hypothesized that the essentiality scores could be important and should be considered in gene functional analysis. For this purpose, here we proposed WEAT (https://www.cuilab.cn/weat/), a weighted gene set enrichment algorithm and online tool by weighting genes using essentiality scores. We confirmed the usefulness of WEAT using two case studies, the functional analysis of one aging-related gene list and one gene list involved in Lung Squamous Cell Carcinoma (LUSC). Finally, we believe that the WEAT method and tool could provide more possibilities for further exploring the functions of given gene lists.

bioinformatics↗