Biology subjects

chen, z.

Publications and source records attributed to chen, z..

9 recordsLinked to original sources

bioRxiv2026

The U6 snRNA capping enzyme Amus/MePCE is required for the stability of U6atac and the processing of introns with features of both major and minor classes

Over 99% of the introns in humans are removed by the major spliceosome with the U6 snRNA as the catalytic component while the rest 1% by the minor spliceosome containing U6atac. Recent evidence supports mechanistic interactions between the two splicing pathways even though they have been considered as operating in parallel. Here we report a unique genetic condition in which both splicing pathways are partially impaired, and present evidence supporting inter-pathway interactions. We recently showed that the Drosophila Amus protein and its mammalian homolog MePCE serve as the methyltransferase of U6 and protect its stability. We show here that U6atac is greatly reduced under the same amus or mepce mutant backgrounds, suggesting Amus/MePCE serves the same protective function for U6atac. Interestingly, the processing of canonical minor introns is not significantly affected in the mutants, suggesting that a minimal amount of U6atac is sufficient for those reactions. In contrast, the splicing of a second class of minor spliceosome sensitive introns are inhibited. These introns harbor splice sites different from the minor consensus even though they interact favorably with the minor spliceosome as shown by others. Interestingly, most members of this class of minor-like introns are evolutionarily younger than their canonical counterparts, and our in-depth analysis of one such intron supports that some of them might be functionally neutral. Our study provides empirical evidence supporting the existence of a class of introns jointly regulated by the two splicing pathways, and revealing additional complexity in the functional evolution of minor splicing.

genetics↗

bioRxiv2026

Multimolecular proofreading overcomes the activity-fidelity trade-off

Accurate signal processing is essential for proper cell functions, and can be achieved through kinetic proofreading, where an enzyme undergoes sequential state transitions and irreversible deactivation to enable high fidelity. However, synthetically constructing a biological proofreading system has been hindered by the difficulty in engineering single molecular state transitions. Here, we designed a protein circuit that combines diffusion and endocytosis to enable kinetic proofreading at the multimolecular level, without the conservation of total enzymes implicitly assumed in classic kinetic proofreading. Simulations revealed a previously overlooked yet experimentally crucial trade-off between circuit activity and fidelity, and theoretical analysis confirmed it to be fundamental in all kinetic proofreading systems. By integrating self-activation and mutual inhibition mechanisms, the circuit overcomes this activity-fidelity trade-off within biologically plausible parameter regimes. Our results extend proofreading schemes from single enzymes to a multimolecular context, and represent a practical and generalizable strategy for constructing high-fidelity synthetic biological circuits. HIGHLIGHTSO_LIWe design a multimolecular and multicellular proofreading circuit C_LIO_LIA previously overlooked yet practically relevant trade-off arises between circuit activity and fidelity C_LIO_LIThe activity-fidelity trade-off is fundamental in all kinetic proofreading circuits C_LIO_LISelf-activation and mutual inhibition mechanisms collectively overcome the activity-fidelity trade-off C_LI

synthetic biology↗

bioRxiv2025

Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI.

Staphylococcus aureus infections have already become a major threat to public health worldwide. Drug resistance and biofilm formation are two critical factors that significantly affect the efficacy of the antimicrobial treatment of S. aureus infections using conventional antibiotics. Therefore, the discovery of novel antimicrobial agents with potent antibacterial and antibiofilm activity has become a hotspot in recent years. Here, we first demonstrated the remarkable inhibitory activity of AZD-5991, a selective Mcl-1 inhibitor, against S. aureus. The MIC50 and MIC90 of AZD-5991 against S. aureus were 12.5 M, and AZD-5991 significantly inhibited the growth of S. aureus at a subinhibitory concentration of 1/2 x MIC. Besides, AZD-5991 displayed bactericidal activity and a robust capacity for inhibiting biofilm formation against S. aureus with very low drug toxicity against host cell lines. Our data demonstrated the disruption of S.aureus cell integrity by AZD-5991 through membrane permeability assays and the ingredients of the bacterial phospholipids could neutralize the antibacterial activity of AZD-5991. Moreover, whole-genome sequencing and proteomic analysis were also applied to gain insights into the possible impact of AZD-5991 on the fatty metabolism of S. aureus. Furthermore, the antibacterial activity of AZD-5991 was significantly elevated by exogenous fatty acids linoleic acid (C18:2 {Delta} 9,12) and arachidonic acid (C20:4 {Delta} 5,8,11,14). Lastly, the biolayer interferometry assay supported the direct interaction of AZD-5991 with FabI, a necessary protein related closely to bacterial growth and fatty acid metabolism. Conclusively, this study suggests that AZD-5991 could inhibit the planktonic growth and biofilm formation of S. aureus by disrupting the cell membrane and targeting FabI. AZD-5991 might be a promising new antibiotic candidate for the antimicrobial treatment of S. aureus infections resistant to traditional clinical drugs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/638150v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@658444org.highwire.dtl.DTLVardef@cea949org.highwire.dtl.DTLVardef@1cc003dorg.highwire.dtl.DTLVardef@23de22_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Amino acid transporter SLC7A5 regulates Paneth cell function to affect the intestinal inflammatory response

The intestine is critical for not only processing and resorbing nutrients but also protecting the organism from the environment. These functions are mainly carried out by the epithelium, which is constantly being self-renewed. Many genes and pathways can influence intestinal epithelial cell proliferation. Among them is mTORC1, whose activation increases cell proliferation. Here, we report the first intestinal epithelial cell-specific knockout ({Delta}IEC) of an amino acid transporter capable of activating mTORC1. We show that the transporter, SLC7A5, is highly expressed in mouse intestinal crypt and Slc7a5{Delta}IEC reduces mTORC1 signaling. Surprisingly, Slc7a5{Delta}IEC mice have increased cell proliferation but reduced secretory cells, particularly mature Paneth cells. scRNA-seq and electron microscopic analyses revealed dedifferentiation of Paneth cells in Slc7a5{Delta}IEC mice, leading to markedly reduced secretory granules with little effect on Paneth cell number. We further show that Slc7a5{Delta}IEC mice are prone to experimental colitis. Thus, SLC7A5 regulates secretory cell differentiation to affect stem cell niche and/or inflammatory response to regulate cell proliferation.

immunology↗

bioRxiv2022

TIGER: A Web Portal of Tumor Immunotherapy Gene Expression Resource

Immunotherapy is a promising cancer treatment method, but only a few patients benefit from it. Developing new immunotherapy strategies and effective biomarkers of response and resistance is urgent. Recent high-throughput bulk and single-cell gene expression profiling technologies have generated valuable resources in these regards. However, these resources are not well organized and systematic analysis is difficult. Here, we present TIGER, a tumor immunotherapy gene expression resource, which contains bulk transcriptome data of 1508 tumor samples with immunotherapy clinical outcome and 11,057 tumor/normal samples without immunotherapy clinical outcome, as well as single-cell transcriptome data of 2,116,945 immune cells of 655 samples. TIGER provides many useful modules to analyze the collected data and user-provided data. Using the resource in TIGER, we identified a tumor enriched subset of CD4+ T cells. Melanoma patients with higher signature score of this subset have significantly better response and survival under immunotherapy. We believe that TIGER will be helpful for understanding anti-tumor immunity mechanisms and discovering effective biomarkers. TIGER is freely accessible at http://tiger.canceromics.org/.

bioinformatics↗

bioRxiv2021

Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome

Chromatin remodeler ALC1 (amplification in liver cancer 1) is crucial for repairing damaged DNA. It is autoinhibited and activated by nucleosomal epitopes. However, the mechanisms by which ALC1 is regulated remain unclear. Here we report the crystal structure of human ALC1 and the cryoEM structure bound to the nucleosome. The structure shows the macro domain of ALC1 binds to lobe 2 of the ATPase motor, sequestering two elements for nucleosome recognition, explaining the autoinhibition mechanism of the enzyme. The H4 tail competes with the macro domain for lobe 2-binding, explaining the requirement for this nucleosomal epitope for ALC1 activation. A dual-arginine-anchor motif of ALC1 recognizes the acidic pocket of the nucleosome, which is critical for chromatin remodeling in vitro. Together, our findings illustrate the structures of ALC1 and shed light on its regulation mechanisms, paving the way for the discovery of drugs targeting ALC1 for the treatment of cancer.

biochemistry↗

bioRxiv2020

Full-length genome sequence of segmented RNA virus from ticks was obtained using small RNA sequencing data

In 2014, A novel tick-borne virus of the genus Flavivirus was first reported from the Mogiana region in Brazil. This virus was named the Mogiana tick virus (MGTV). Later, MGTV was also named as Jingmen tick virus (JMTV), Kindia tick virus (KDTV), Guangxi tick virus (GXTV) etc. In the present study, we used small RNA sequencing (sRNA-seq) to detect viruses in ticks and detected MGTV in Amblyomma testudinarium ticks, which had been captured in Yunnan province of China in the year of 2016. The full-length genome sequence of a new MGTV strain Yunnan2016 (GenBank: MT080097, MT080098, MT080099 and MT080100) was obtained and recommended to be included into the NCBI RefSeq database for the future studies of MGTV. Our phylogenetic analyses showed that viruses named MGTV, JMTV, KDTV and GXTV are monophyletic: the MGTV group (lineage) of viruses. We show, for the first time, that 5' and 3' sRNAs can be used to obtain full-length sequences of the 5 and 3 ends of, but not limited to genome sequences of RNA viruses. And we proved the feasibility of using the sRNA-seq based method for the detection of viruses in a sample containing miniscule RNA.

bioinformatics↗

bioRxiv2019

GNMFLMI: Graph Regularized Nonnegative Matrix Factorization for Predicting LncRNA-MiRNA Interactions

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been involved in various biological processes. Emerging evidence suggests that the interactions between lncRNAs and miRNAs play an important role in regulating of genes and the development of many diseases. Due to the limited scale of known lncRNA-miRNA interactions, and expensive time and labor costs for identifying them by biological experiments, more accurate and efficient lncRNA-miRNA interactions computational prediction approach urgently need to be developed. In this work, we proposed a novel computational method, GNMFLMI, to predict lncRNA-miRNA interactions using graph regularized nonnegative matrix factorization. More specifically, the similarities both lncRNA and miRNA are calculated based on known interaction information and their sequence information. Then, the affinity graphs for lncRNAs and miRNAs are constructed using the p-nearest neighbors, respectively. Finally, a graph regularized nonnegative matrix factorization model is developed to accurately identify potential interactions between lncRNAs and miRNAs. To evaluate the performance of GNMFLMI, five-fold cross validation experiments are carried out. GNMFLMI achieves the AUC value of 0.9769 which outperforms the compared methods NMF and CNMF. In the case studies for lncRNA nonhsat159254.1 and miRNA hsa-mir-544a, 20 and 16 of the top-20 associations predicted by GNMFLMI are confirmed, respectively. Rigorous experimental results demonstrate that GNMFLMI can effectively predict novel lncRNA-miRNA interactions, which can provide guidance for relevant biomedical research.

bioinformatics↗

bioRxiv2018

In Vitro Activities of Daptomycin Combined with Fosfomycin or Rifampin on Planktonic and Adherent Linezolid-resistant Enterococcus faecalis

This study aimed to explore daptomycin combined with fosfomycin or rifampin against the planktonic and adherent linezolid-resistant isolates of Enterococcus faecalis. Four linezolid-resistant isolates of E. faecalis which formed biofilms were collected for this study. Biofilm biomasses were detected by crystal violet staining. The adherent cells in the mature biofilms were counted by CFU numbers and observed by confocal laser scanning microscope (CLSM). In time-killing studies, daptomycin combined with fosfomycin or rifampin (4xMIC) demonstrated bactericidal activities on the planktonic cells, and daptomycin combined with fosfomycin killed more planktonic cells (at least 2-log10 CFU/ml) than daptomycin or fosfomycin alone. Daptomycin alone showed activities against the mature biofilms, and daptomycin combined with fosfomycin (16xMIC) demonstrated significantly more activity than daptomycin or fosfomycin alone against the mature biofilms in three of the four isolates. Daptomycin alone effectively killed the adherent cells, and daptomycin combined with fosfomycin (16xMIC) killed more adherent cells than daptomycin or fosfomycin alone in these mature biofilms. The high concentrations of daptomycin (512 mg/L) combined with fosfomycin indicated more activity than 16xMIC of daptomycin combined with fosfomycin on the adherent cells and the mature biofilms. The addition of rifampin increased the activity of daptomycin against the biofilms and the adherent cells of FB-14 and FB-80 isolates, but was not observed in FB-1 and FB-2 isolates. In conclusion, daptomycin combined with fosfomycin works effectively against the planktonic and adherent linezolid-resistant isolates of E. faecalis. The role of rifampin in these linezolid-resistant isolates is discrepant and needs more studies.

microbiology↗