Biology subjects

Bian, Q.

Publications and source records attributed to Bian, Q..

9 recordsLinked to original sources

bioRxiv2026

MYRF drives heterochronic miRNAs and LIN-42, and amplifies oscillatory programs for stage transitions

Larval development in C. elegans proceeds through discrete stages, yet the mechanisms that drive stage transitions remain incompletely defined. Here, we identify the transmembrane transcription factor MYRF as a master temporal regulator essential for larval progression. MYRF cleavage and nuclear accumulation oscillate across larval stages, peaking during mid-to-late intermolt phases. MYRF directly activates key heterochronic microRNAs--including lin-4, mir-48/241/84, and let-7--and amplifies the oscillatory gene network by promoting central regulators such as nhr-23. MYRF loss-of-function or acute depletion suppresses and flattens this network, causing developmental arrest during the late intermolt phase of each larval cycle and stalling molting, seam cell division, and vulval morphogenesis. Notably, MYRF oscillations precede and induce activation of lin-42/Period, which feeds back to repress myrf, sharpening oscillatory precision. Together, these findings establish MYRF as a central driver of larval stage transitions, coupling microRNA-conferred temporal identity with an amplifier-based logic that executes stage- and phase-specific developmental programs.

developmental biology↗

bioRxiv2026

Hidden stop codons orchestrate mRNA fate by ambushing ribosomal frameshifting associated with codon usage

In eukaryotes, the mRNA stability is generally shaped by codon usage bias, the uneven preferences for synonymous codons, in a translation-dependent manner. However, the conserved mechanism linking codon to mRNA decay remains elusive. Hidden stop codons (HSCs), defined as stop codons located in the +1 or -1 frame relative to canonical ORF, are widespread across all genomes but largely uncharacterized. Here, we demonstrate that in both fungi and human cells, HSCs play an conserved and mechanistic role in promoting mRNA decay by rapidly terminating out-of-frame translation promoted by nonoptimal codons, primarily through +1 ribosomal frameshifting. In the filamentous fungus Neurospora crassa, partially deleting HSCs via synonymous substitutions in the clock gene frequency increases mRNA stability and disrupts circadian rhythmicity. In human cells, acute depletion of translation termination factor eRF1 impairs recognition of HSCs, leading to global stabilization of mRNAs enriched in nonoptimal codons and HSCs. In both Neurospora and humans, these mRNAs are in part degraded through the NMD pathway via UPF1. Collectively, these findings suggest that in eukaryotes, HSCs serve as surveillance elements to monitor ribosomal frameshifting and out-of-translation promoted by nonoptimal codons, thereby initiating mRNA decay through NMD.

molecular biology↗

bioRxiv2024

The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells

The mechanisms by which bone marrow stromal cells (BMSCs) maintain multilineage potency in vitro remain elusive. To identify the transcriptional regulatory circuits that contribute to BMSC multipotency, we performed paired single-nucleus multiomics of the expansion of freshly isolated BMSCs and of BMSCs undergoing tri-lineage differentiation. By computationally reconstructing the regulatory programs associated with initial stages of differentiation and early expansion, we identified the TEAD family of transcription factors, which is inhibited by Hippo signaling, as highly active in the BMSC in vitro multipotent state. Pharmacological inhibition of TEAD enhanced BMSC osteogenic and adipogenic differentiation, whereas its activation maintained BMSCs in an undifferentiated state, supporting a model whereby isolation of BMSCs coincides with a TEAD-controlled transcriptional state linked to multipotency. Our study highlights the Hippo pathway as a pivotal regulator of BMSC multipotency, and our regulatory network inferences are a reservoir of testable hypotheses that link transcription factors and their regulons to specific aspects of BMSC behavior.

genomics↗

bioRxiv2024

ROS Mediated the Photodynamic Antibacterial of Vibrio vulnificus by a DNA-Targeted Molecular Rotor Probe

Vibrio vulnificus, a highly pathogenic Gram-negative bacterium, is capable of inducing sepsis, necrotizing fasciitis, and skin and soft tissue infections through contact with wounds. Currently, the majority of V. vulnificus strains have developed resistance to multiple drugs, highlighting the critical necessity for the development of novel therapeutics capable of effectively targeting and eradicating this bacterium. In recent years, material molecules have emerged as promising antimicrobial agents. This study introduces a novel molecular fluorescent probe, BDTP, which demonstrates a wide-ranging antimicrobial effect against both Gram-negative and Gram-positive bacteria while exhibiting minimal toxicity to normal mammalian cells. Of particular significance is BDTPs ability to rapidly detect V. vulnificus, bind to bacterial DNA, and exhibit fluorescence monitoring behavior. Furthermore, BDTP displays enhanced photodynamic antibacterial activity when exposed to white light irradiation. Under a low dose of white light (15mW cm-2), the killing efficiency of V. vulnificus irradiated with 4uM for 10 minutes was more than 99.8%. Moreover, it could significantly inhibit and eliminate the biofilm formed by V. vulnificus. It can induce the production of reactive oxygen species (ROS) in V. vulnificus cells, leading to bacterial cell damage. More importantly, BDTP significantly promoted the healing of infected wounds in an animal model of V. vulnificus infection. Therefore, BDTP shows great promise as a potent antibacterial agent against V. vulnificus infection.

microbiology↗

bioRxiv2021

Signaling and transcriptional networks governing late synovial joint development

BackgroundDuring synovial joint development, cavitation marks the end of the emergence of new cell types and the onset of the consolidation of cell type specific programs. However, the transcriptional programs that regulate this crucial stage prior to joint maturation are incompletely characterized. Gdf5-lineage cells give rise to the majority of joint constituents such as articular cartilage, meniscus, ligament, and tendon. Therefore, to explore pre-maturation of the synovial joint, we performed single cell RNA-Seq analysis of 1,306 Gdf5-lineage cells from the murine knee joint at E17.5. ResultsUsing computational analytics and in situ hybridization, we identified nine sub-states contributing to articular cartilage, meniscus, cruciate ligament, synovium, lining, and surrounding fibrous tissue. We identified a common progenitor population that is predicted to give rise to ligamentaocytes, articular chondrocytes, and lining cells. We further found that while a large number of signaling pathways orchestrate the differentiation of this progenitor to either ligamentocytes or to lining cells, only continued FGF signaling guides these cells to a default chondrocyte fate. ConclusionsOur single cell transcriptional atlas is a resource that can be used to better understand and further study synovial joint development and the reactivation of embryonic programs in diseases such as osteoarthritis.

developmental biology↗

bioRxiv2021

Reconstruction of dynamic regulatory networks reveals signaling-induced topology changes associated with germ layer specification

Elucidating regulatory relationships between transcription factors (TFs) and target genes is fundamental to understanding how cells control their identity and behavior. Computational gene regulatory network (GRN) reconstruction methods aim to map this control by inferring relationships from transcriptomic data. Unfortunately, existing methods are imprecise, may be computationally burdensome, and do not uncover how networks transition from one topology to another. Here we present Epoch, a computational network reconstruction tool that leverages single cell transcriptomics to infer dynamic network structures. Epoch performs favorably when benchmarked using data derived from in vivo, in vitro, and in silico sources. To illustrate the usefulness of Epoch, we applied it to identify the dynamic networks underpinning directed differentiation of mouse embryonic stem cells (ESC) guided by multiple primitive streak induction treatments. Our analysis demonstrates that modulating signaling pathways drives topological network changes that shape cell fate potential. We also find that Peg3 is a central contributor to the rewiring of the pluripotency network to favor mesoderm specification. By integrating signaling pathways with GRN structures, we traced how Wnt activation and PI3K suppression govern mesoderm and endoderm specification, respectively. Finally, we compare the networks established in in vitro directed differentiation of ESCs to those in in vivo gastrulation and mesoderm specification. The methods presented here are available in the R package Epoch, and provide a foundation for future work in understanding the biological implications of dynamic regulatory structures.

systems biology↗

bioRxiv2020

A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2

Mutations and transient conformational movements of receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable, present immune escape routes to SARS-CoV-2. To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, combination of RBD-targeting NAbs and NTD-binding NAb, FC05, dramatically enhanced the neutralization potency in cell-based assays and animal model. Results of competitive SPR assays and cryo-EM structures of Fabs bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in NTD and RBD of S, when immunized in rabbits elicited potent protective immune responses against SARS-CoV-2. These results provide a proof-of-concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD. One sentence summaryImmunogens identified in the NTD and RBD of the SARS-CoV-2 spike protein using a cocktail of non-competing NAbs when injected in rabbits elicited a potent protective immune response against SARS-CoV-2.

microbiology↗

bioRxiv2020

Evaluating the transcriptional fidelity of cancer models

BackgroundCancer researchers use cell lines, patient derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derives from the fidelity with which it represents the tumor type under investigation, however, the extent to which this is true is often unclear. The preponderance of models and the ability to readily generate new ones has created a demand for tools that can measure the extent and ways in which cancer models resemble or diverge from native tumors. MethodsWe developed a machine learning based computational tool, CancerCellNet, that measures the similarity of cancer models to 22 naturally occurring tumor types and 36 subtypes, in a platform and species agnostic manner. We applied this tool to 657 cancer cell lines, 415 patient derived xenografts, 26 distinct genetically engineered mouse models, and 131 tumoroids. We validated CancerCellNet by application to independent data, and we tested several predictions with immunofluorescence. ResultsWe have documented the cancer models with the greatest transcriptional fidelity to natural tumors, we have identified cancers underserved by adequate models, and we have found models with annotations that do not match their classification. By comparing models across modalities, we report that, on average, genetically engineered mice and tumoroids have higher transcriptional fidelity than patient derived xenografts and cell lines in four out of five tumor types. However, several patient derived xenografts and tumoroids have classification scores that are on par with native tumors, highlighting both their potential as faithful model classes and their heterogeneity. ConclusionsCancerCellNet enables the rapid assessment of transcriptional fidelity of tumor models. We have made CancerCellNet available as freely downloadable software and as a web application that can be applied to new cancer models that allows for direct comparison to the cancer models evaluated here.

bioinformatics↗

bioRxiv2019

A single cell transcriptional atlas of early synovial joint development

Synovial joint development begins with the formation of the interzone, a region of condensed mesenchymal cells at the site of the prospective joint. Recently, lineage tracing strategies have revealed that Gdf5-lineage cells native to and from outside the interzone contribute to most, if not all, of the major joint components. However, there is limited knowledge of the specific transcriptional and signaling programs that regulate interzone formation and fate diversification of synovial joint constituents. To address this, we have performed single cell RNA-Seq analysis of 6,202 synovial joint progenitor cells from the developing murine knee joint from E12.5 to E15.5. By using a combination of computational analytics, in situ hybridization, and functional analysis of prospectively isolated populations, we have inferred the underlying transcriptional networks of the major developmental paths for joint progenitors. Our freely available single cell transcriptional atlas will serve as a resource for the community to uncover transcriptional programs and cell interactions that regulate synovial joint development.

developmental biology↗