Biology subjects

Di, W.

Publications and source records attributed to Di, W..

7 recordsLinked to original sources

bioRxiv2025

CDK12 condensation in nuclear speckles confers sensitivity to cyclin K molecular glue degraders

Transcriptional machinery often operates in the configuration of biomolecular condensates, presenting emerging opportunities to develop therapies targeting transcriptionally addicted malignancies. In this study, we discovered that cyclin-dependent kinase 12 (CDK12), a key regulator of transcription elongation, formed dynamic liquid-like droplets within nuclear speckles, a process enhanced by high CDK12 expression and CDK12 inhibitor treatment. Recognizing this unique property, we rationally designed ZSQ253, a modular cyclin K molecular glue degrader that coupled binding moieties for both CDK12 and DDB1. By promoting phase separation-driven assembly and subsequent proteasomal degradation of the CDK12-cyclin K complex, ZSQ253 interfered with oncogenic transcription and demonstrated potent antitumor capability. Further structure-guided optimization yielded HQY1428, a derivative with a multi-site gluing effect and improved drug activity. Given the frequent genomic co-amplification of CDK12 and ERBB2 across diverse human cancers, we showed that combining HQY1428 with HER2 inhibitors provided synergistic therapeutic benefits. Collectively, our findings establish CDK12 condensation within nuclear speckles as an exploitable vulnerability, and introduce a novel mechanism of action underlying cyclin K molecular glue degraders.

cancer biology↗

bioRxiv2024

De novo genome assembly of Myricaria laxiflora provides insights into its molecular mechanisms under flooding stress

M. laxiflora is an endangered plant distributed in the Yangtze River floodplain of China, which often suffers from flood hazards during its growth and development. Due to the lack of a reference genome for M. laxiflora, the molecular regulatory mechanism of its waterlogging stress remains unclear. Here, we report for the first time the high-quality reference genome of M. laxiflora by using HiFi sequencing and Hi-C. The total assembly size of the M. laxiflora genome was 1.29 Gb with a scaffold N50 size of 29.5 Mb. A total of 23,666 genes encoding proteins and 5,457 ncRNA were predicted in this reference genome. In the M. laxiflora genome, a total of 101 MylAP2/ERF genes were identified and divided into 5 subgroups. Many MeJA responsive elements, ABA responsive elements, and hypoxia responsive elements were found in the promoter regions of these MylAP2/ERF genes. Based on transcriptome data analysis, a total of 74 MylAP2/ERF genes can respond to flooding stress. Meanwhile, it was found that three genes (MylAP2/ERF49/78/91) which belong to the same branch with RAP2.2 gene exhibited different expression trends under flooding stress. Our results provide valuable information on the molecular regulatory mechanism of flooding stress in M. laxiflora.

plant biology↗

bioRxiv2023

AVM: a manually curated database of aerosol-transmitted virus mutations, human diseases, and drugs

Aerosol-transmitted viruses, with aerosol particles floating in the air to long distances, have the characteristics of strong infectivity and wide spread that is difficult to control. They cause various human diseases, posing a huge threat to human health. Some mutations can increase the transmissibility and virulence of the strain, which can reduce the protection of vaccines and weaken efficacy of antiviral drugs. Here, we established a manually curated database, AVM, to store this information. The current version of the AVM contains a total of 42,041 virus mutations, including 2613 immune escape mutations, 45 clinical information datasets, and 407 drugs, antibodies, or vaccines. In addition, we recorded 88 human diseases associated with viruses, and we found that the same virus can attack multiple target organs in the body and lead to diversified diseases. Further, the AVM database offers a straightforward user interface to expediently browse, retrieve, and download details. The AVM database is a comprehensive resource that provides timely and valuable assistance regarding the transmission, treatment, and related diseases of aerosol-transmitted viruses (http://bio-bigdata.hrbmu.edu.cn/AVM or http://www.bio-bigdata.center/AVM).

bioinformatics↗

bioRxiv2021

High-quality reference genome of Fasciola gigantica: Insights into the genomic signatures of transposon-mediated evolution and specific parasitic adaption in tropical regions

Fasciola gigantica and Fasciola hepatica are causative pathogens of fascioliasis, with the widest latitudinal, longitudinal, and altitudinal distribution; however, among parasites, they have the largest sequenced genomes, hindering genomic research. In the present study, we used various sequencing and assembly technologies to generate a new high-quality Fasciola gigantica reference genome. We improved the integration of gene structure prediction, and identified two independent transposable element expansion events contributing to (1) the speciation between Fasciola and Fasciolopsis during the Cretaceous-Paleogene boundary mass extinction, and (2) the habitat switch to the liver during the Paleocene-Eocene Thermal Maximum, accompanied by gene length increment. Long interspersed element (LINE) duplication contributed to the second transposon-mediated alteration, showing an obvious trend of insertion into gene regions, regardless of strong purifying selection. Gene ontology analysis of genes with long LINE insertions identified membrane-associated and vesicle secretion process proteins, further implicating the functional alteration of the gene network. We identified 852 excretory/secretory proteins and 3300 protein-protein interactions between Fasciola gigantica and its host. Among them, copper/zinc superoxide dismutase genes, with specific gene copy number variations, might play a central role in the phase I detoxification process. Analysis of 559 single-copy orthologs suggested that Fasciola gigantica and Fasciola hepatica diverged at 11.8 Ma near the Middle and Late Miocene Epoch boundary. We identified 98 rapidly evolving gene families, including actin and aquaporin, which might explain the large body size and the parasitic adaptive character resulting in these liver flukes becoming epidemic in tropical and subtropical regions.

genomics↗

bioRxiv2020

Chromatin accessibility profiles of castration-resistant prostate cancers reveal novel subtypes and therapeutic vulnerabilities

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR)-dependence due to lineage plasticity, which has become more prevalent, leads to clinically highly aggressive tumors with few therapeutic options and is mechanistically poorly defined. To identify the master transcription factors (TFs) of CRPC in a subtype-specific manner, we derived and collected 29 metastatic human prostate cancer organoids and cell lines, and generated ATAC-seq, RNA-seq and DNA sequencing data. We identified four subtypes and their master TFs using novel computational algorithms: AR-dependent; Wnt-dependent, driven by TCF; neuroendocrine, driven by ASCL1 and NEUROD1 and stem cell-like (SCL), driven by the AP-1 family. The transcriptomic signatures of these four subtypes enabled the classification of 370 patients. We find that AP-1 co-operates with the inhibitable YAP/TAZ/TEAD pathway in the SCL subtype, the second most common group of CRPC tumors after AR-dependent. Together, this molecular classification reveals new drug targets and can potentially guide therapeutic decisions.

cancer biology↗

bioRxiv2020

Bright Near-infrared Anti-Stokes Fluorescence of ICG under Low Power CW Laser Excitation and its Applications in Bioimaging

Anti-Stokes fluorescence was observed in ICG, a molecule approved by the FDA for clinical use. The wavelengths of its fluorescence are mainly located in the near-infrared band of 800 nm~900 nm, with a high quantum yield up to 8%. In order to know its generation mechanism, based on multi-photon absorption (MPA) theory, thermally activated delayed fluorescence (TADF) theory and hot band absorption theory, its power dependence, temperature dependence of absorption spectra and fluorescence spectra, and fluorescence lifetime were measured. Its generation mechanism was finally determined to be hot band absorption process. Since ICG showed bright anti-Stokes fluorescence in near-infrared region, which offers substantially longer penetration depth in biological tissues than visible light, excellent photostability and biosafety, we applied it to in vivo imaging and compared it with upconversion nanoparticles (UCNPs). The result is that ICG exhibited much stronger fluorescence than UCNPs, providing more anatomical information of samples. This contributes to a better choice for anti-Stokes fluorescence bioimaging.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioengineering↗

bioRxiv2020

ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

While cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer pro-luminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we have identified that ERG highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibits its normal plasticity to transdifferentiate into basal lineage and ERG supersedes PTEN-loss which favors basal differentiation. ERG knock-out disrupted prostate cell luminal differentiation, whereas AR knock-out had no such effects. Trp63 is a known master regulator of prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG binds and inhibits the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG orchestrates chromatin interactions and regulates prostate cell lineage toward pro-luminal program, as its fundamental role on lineage differentiation in prostate cancer initiation.

cancer biology↗