Biology subjects

Cui, M.

Publications and source records attributed to Cui, M..

62 records · Page 4Linked to original sources

bioRxiv2019

A novel antiviral lncRNA EDAL shields a T309 O-GlcNAcylation site to promote EZH2 degradation

The central nervous system (CNS) is vulnerable for viral infection, yet few host factors in the CNS are known to defend invasion by neurotropic viruses. We report here that multiple neurotropic viruses, including rabies virus (RABV), vesicular stomatitis virus (VSV), Semliki Forest virus (SFV) and herpes simplex virus 1 (HSV-1), elicit the neuronal expression of a host-encoded lncRNA EDAL. EDAL inhibits the replication of these neurotropic viruses in neuronal cells and RABV infection in mouse brains. EDAL binds to the conserved histone methyltransferase enhancer of zest homolog 2 (EZH2) and specifically causes EZH2 degradation via lysosomes, reducing the cellular H3K27me3 level. The antiviral function of EDAL resides in a 56-nt antiviral substructure through which its 18-nt helix-loop intimately contacts multiple EZH2 sites surrounding T309, a known O-GlcNAcylation site. EDAL positively regulate the transcription of Pcp4l1 encoding a 10 kDa peptide, which inhibits the replication of mutiple neurotropic viruses. Our findings proposed a model in which a neuronal lncRNA can exert an effective antiviral function via blocking a specific O-GlcNAcylation that determines EZH2 lysosomal degradation.

microbiology↗

bioRxiv2019

PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates

Tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory mechanism for exocytosis. However, the participation of protein tyrosine phosphatases (PTPs) in different exocytosis stages has not been defined. Here we demonstrated that PTP-MEG2 controls multiple steps of catecholamine secretion. Biochemical and crystallographic analyses revealed key residues that the interactions between govern the PTP-MEG2 and NSF-pY83 site, specify PTP-MEG2 substrate selectivity and modulate the fusion of catecholamine-containing vesicles. Unexpectedly, delineation of PTP-MEG2 mutants along with the NSF binding interface revealed that PTP-MEG2 controls the fusion pore opening through non-NSF dependent mechanisms. Utilizing bioinformatics search and biochemical and electrochemical screening approaches, we discovered that PTP-MEG2 regulates the opening and extension of the fusion pore by dephosphorylating the DYNAMIN2-pY125 and MUNC18-1-pY145 site. Further structural and biochemical analysis confirmed the interaction of PTP-MEG2 with MUNC18-1-pY145 or DYNAMIN2-pY125 through a distinct structural basis compared with that of the NSF-pY83 site. Our studies extended mechanistic insights in complex exocytosis processes. HIGHLIGHTSPTP-MEG2 regulates multiple steps of exocytosis. A crystal structure of the PTP-MEG2/phosphor-NSF-pY83 segment was obtained. Functional delineation of the PTP-MEG2/NSF interface led to the discovery of new PTP-MEG2 substrates. PTP-MEG2 regulates fusion pore opening and extension through the DYNAMIN2-pY125 site and MUNC18-1 pY145 site. The distinct structural basis of the recognition of substrates by PTP-MEG2 allows selective inhibitor design.

cell biology↗

bioRxiv2019

Winner(s)-take-all: nonlinear amplification of DNA-encoded library

Information processing functions are essential for biological organisms to perceive and react to their complex enviornment, as well as for human to analyze and rationalize them. While our brain has an extraordinary power to process complex information, winner(s)-take-all computation is one of the simplest models of lateral inhibition and competition among biological neurons. It has been implemented as DNA-based neural networks, for example, to mimic pattern recognition. However, the utility of DNA-based computation in information processing for real biotechnological applications remains to be demonstrated. In this paper, we developed a winner(s)-take-all method for non-linear amplification of mixtures of DNA sequences. Unlike conventional biological experiments, selected species were not directly subjected to analysis. Instead, parallel computation among myriad of different DNA sequences was carried out with a neural network-inspired winner-take-all function, to reduce the information complexity. The method could be used for various oligonucleotide-encoded libraries, as we have demonstrated its application in decoding and data analysis for selection experiment with DNA-encoded chemical library against protein target.

bioengineering↗

bioRxiv2019

Incorporating Randomness into DNA Steganography to Realize Secondary Secret key, Self-destruction, and Quantum Key Distribution-like Function

DNA has become a promising candidate as future data storage medium, which makes DNA steganography indispensable in DNA data security. While PCR primers are conventional secret keys in DNA steganography, the information can be read once the primers are intercepted. New steganography approach is needed to make the DNA-encoded information safer, if not unhackable. Herein, by mixing information-carrying DNA with partially degenerated DNA library containing single or multiple restriction sites, we build an additional protective layer, which can be removed by desired restriction enzymes as secondary secret keys. As PCR is inevitable for reading DNA-encrypted information, heating will cause reshuffling and generate endonuclease-resistant mismatched duplexes, especially for DNA with high sequence diversity. Consequently, with the incorporation of randomness, the DNA steganography possesses both quantum key distribution (QKD)-like function for detecting PCR by an interceptor and self-destructive property. With a DNA-ink incorporating the steganography, the authenticity of a writing can be confirmed only by authorized person with the knowledge of all embedded keys.

synthetic biology↗

bioRxiv2019

Degradation of miR-466d-3p by JEV NS3 facilitates viral replication and IL-1β expression

Previous studies revealed that Japanese encephalitis virus (JEV) infection alters the expression of miRNA in central nervous system (CNS). However, the mechanism of JEV infection contributes to the regulation of miRNAs in CNS remain obscure. Here, we found that a global degradation of mature miRNA in mouse brain and neuroblastoma cells after JEV infection. In additional, the integrative analysis of miRNAs and mRNAs suggests that those down-regulated miRNAs are primarily targeted inflammation genes and the miR-466d-3p target the IL-1{beta} which in the middle of those inflammation genes. Transfection of miR-466d-3p decreased the IL-1{beta} expression and inhibited the JEV replication in NA cells. Interestingly, the miR-466d-3p level increased after JEV infection in the presence of cycloheximide, which indicated that viral protein expression reduces miR-466d-3p. Therefore, we generated all the JEV coding protein and demonstrated that NS3 is a potent miRNA suppressor. Furthermore, the NS3 of ZIKA virus, WNV, DENV1 and DENV2 also decreased the expression of miR-466d-3p. The in vitro unwinding assay demonstrated that the NS3 could unwind the pre-miR-466d and induce the disfunction of miRNA. Using computational models and RNA immunoprecipitation assay, we found that arginine-rich domains of NS3 are critical for pre-miRNA binding and the degradation of host miRNAs. Importantly, site-directed mutagenesis of conserved residues revealed that R226G and R202W significantly reduced the binding affinity and degradation of pre-miR-466d. Together, these results extend the helicase of Flavivirus function beyond unwinding duplex RNA to the decay of pre-miRNAs, which provides a new mechanism of NS3 in regulating miRNA pathways and promoting the neuroinflammation.\n\nAuthor SummaryHost miRNAs had been reported to regulate JEV induced inflammation in central nervous system. We found that the NS3 of JEV can reduce most of host miRNA expression. The helicase region of the NS3 specifically binds to precursors of miRNA and lead to incorrect unwinding of precursors of miRNAs which inhibits the function of miRNAs. This observation leads to two major findings. First, we identified the miR-466d-3p targets to the host IL-1{beta} and E protein of JEV, and NS3 degrades the miR-466d-3p to promote the brain inflammation and viral replication. Second, we proved that the arginine on the helicase of NS3 is the main miRNA binding sites, and the miRNA degradation by NS3 was abolished when the R226 and R202 were mutated on the NS3. These findings were also confirmed with NS3 of ZIKA virus, WNV and DENV which could decrease the expression level of miR-466d-3p to enhance the inflammation. Our study provides new insights into the molecular mechanism of encephalitis caused by JEV, and reveals several amino acid sites to further attenuate the JEV vaccine.

microbiology↗

bioRxiv2018

A draft reference genome sequence for Scutellaria baicalensis Georgi

Scutellaria baicalensis Georgi is an important medicinal plant used worldwide. Information about the genome of this species is important for scientists studying the metabolic pathways that synthesise the bioactive compounds in this plant. Here, we report a draft reference genome sequence for S. baicalensis obtained by a combination of Illumina and PacBio sequencing, which was assembled using 10 X Genomics and Hi-C technologies. We assembled 386.63 Mb of the 408.14 Mb genome, amounting to about 94.73% of the total genome size, and the sequences were anchored onto 9 pseudochromosomes with a super-N50 of 33.2 Mb. The reference genome sequence of S. baicalensis offers an important foundation for understanding the biosynthetic pathways for bioactive compounds in this medicinal plant and for its improvement through molecular breeding.

plant biology↗

bioRxiv2018

Fungal polysaccharopeptides reduce obesity by richness of specific microbiota and modulation of lipid metabolism

The prevalence of obesity and related disorders has vastly increased throughout the world and prevention of such circumstances thus represents a major challenge. Here, we show that protein-bound {beta}-glucan (PBG), one representative of Coriolus versicolor polysaccharopeptides which are broadly used as immune boosters and clinically implicated in treatment of cancers and chronic hepatitis, could be a potent anti-obesity agent. PBG could reduce obesity and metabolic inflammation in mice fed with a high-fat diet (HFD). Gut microbiota analysis revealed that PBG markedly increased the abundance of Akkermansia muciniphila although it didnt rescue HFD-induced change in the Firmicutes to Bacteroidetes ratio. It appeared that PBG altered host physiology and created an intestinal microenvironment favorable for A. muciniphila colonization. Fecal transplants from PBG-treated animals in part reduced obesity in recipient HFD-fed mice. Further, PBG was shown to promote lipid metabolism in microbiota-depleted mice. Thus, our data highlights that PBG might exert its anti-obesity effects through a mirobiota-dependent (richness of specific microbiota) and -independent (modulation of lipid metabolism) manner. The fact that Coriolus versicolor polysaccharopeptides are approved oral immune boosters in cancers and chronic hepatitis with well-established safety profiles may accelerate the development of PBG as a novel drug for obesity treatment.

microbiology↗

bioRxiv2017

DNA 5-Hydroxymethylcytosines from Cell-free Circulating DNA as Diagnostic Biomarkers for Human Cancers

DNA modifications such as 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) are epigenetic marks known to affect global gene expression in mammals(1, 2). Given their prevalence in the human genome, close correlation with gene expression, and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology(3), we report here genome-wide 5hmC profiling in circulating cell-free DNA (cfDNA) and in genomic DNA of paired tumor/adjacent tissues collected from a cohort of 90 healthy individuals and 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver, or thyroid cancer. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures in cfDNA were identified with specificity for different cancers. 5hmC-based biomarkers of circulating cfDNA demonstrated highly accurate predictive value for patients with colorectal and gastric cancers versus healthy controls, superior to conventional biomarkers, and comparable to 5hmC biomarkers from tissue biopsies. This new strategy could lead to the development of effective blood-based, minimally-invasive cancer diagnosis and prognosis approaches.

cancer biology↗