Biology subjects

Tse, J.

Publications and source records attributed to Tse, J..

7 recordsLinked to original sources

bioRxiv2025

Single-cell analyses reveal scyphozoan conserved and specific genes contribution during tissue regeneration in two jellyfish

The phylum Cnidaria is the outgroup of Bilateria and includes sea anemones, corals, hydroids, and jellyfish. Cnidarians play crucial ecological roles in marine ecosystems, including the formation of highly diverse and productive coral reefs, and acting as important predator and prey species. Cnidarians are also well known for their remarkable regeneration capacities. Here, we report single-cell RNA sequencing during bell regeneration in two species of scyphozoans or true jellyfish, Aurelia coerulea and Rhopilema esculentum. We delineated 12 cell populations in Aurelia and Rhopilema, and revealed their respective marker genes and enriched gene pathways. Conserved transcription factor Otx and Wnt/ {beta}-catenin signalling pathway genes were identified during regeneration processes. Additionally, we discovered two conserved, sequentially activated modules during regeneration, with stem cells, gastrodermal cells, neural cells, and secretory gland cells modulated in the first phase, followed by cnidocytes in the second phase. Further comparison among cnidarian genomes identified a suite of scyphozoan lineage-specific genes, a subset of which were frequently significantly expressed in cnidocytes in both jellyfish species during the first phase of regeneration. This study reveals key insights into the evolution and contribution of conserved and novel genes to the formation of lineage-specific genetic networks and biological processes.

evolutionary biology↗

bioRxiv2025

Basic-Leucine-Zipper Transcription Factors Regulate Selective Molecular Phenotypes in Regulatory T Cells During IL-2-Induced Activation

Regulatory T (Treg) cells have long been recognized as modulators of immunological tolerance and homeostasis. Previously, we used scRNA-seq to reveal significant Treg heterogeneity in response to IL-2-induced activation. Herein, we leveraged enrichment analyses, as well as bulk and single-nucleus multi-omics in splenic and lung Tregs, to uncover and confirm the importance of transcription factors (TFs) and chromatin remodeling in Treg activation. Multiple bZIP TF motifs showed increased chromatin accessibility post IL-2 treatment, with correlated transcriptional changes resembling Th1 and Th2 molecular phenotypes, further confirmed by spatial ATAC-seq. By combining gene perturbation and CUT&RUN assays before and after Treg stimulation, we show that bZIP TFs, such as BATF and BACH1, are critical to IL-2-induced Treg activation, coordinating epigenetic and transcriptional changes that selectively drive T-helper phenotypes and metabolic pathways.

genomics↗

bioRxiv2024

Discovery of Potent Degraders of the Dengue Virus Envelope Protein

Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the development of small molecule degraders of the envelope (E) protein of dengue virus. We developed two classes of bivalent E-degraders, linking two previously reported E-binding small molecules, GNF-2 and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E degrader with ABL inhibition while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof-of-concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class antiviral drugs.

biochemistry↗

bioRxiv2023

Borrowing Transcriptional Kinases to Activate Apoptosis

Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 - 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.

cancer biology↗

bioRxiv2022

Covalent Disruptor of YAP-TEAD Association Suppresses Defective Hippo Signaling

The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.

cancer biology↗

bioRxiv2022

The kinase activity of the cancer stem cell marker DCLK1 drives gastric cancer progression by reprogramming the stromal tumor landscape

Gastric cancer (GC) is the 3rd leading cause of cancer mortality worldwide, therefore providing novel diagnostic and treatment options is crucial for at risk groups. The serine/threonine kinase doublecortin-like kinase 1 (DCLK1) is a proposed driver of GC with frequent amplification and somatic missense mutations yet the molecular mechanism how DCLK1 mediates tumorigenesis is poorly understood. We report how DCLK1 expression orchestrates complementary cancer cell intrinsic and extrinsic processes leading to a comprehensive pro-invasive and pro-metastatic reprogramming of cancer cells and tumor stroma in a DCLK1 kinase-dependent manner. Mechanistically, we identify the chemokine CXCL12 as a key promoter of the pro-tumorigenic properties downstream of DCLK1. Importantly, inhibition of the DCLK1 kinase domain reverses the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a promising, targetable master regulator of GC. TeaserDCLK1 is a druggable cancer driver of GC

cancer biology↗

bioRxiv2018

Improving on hash-based probabilistic sequence classification using multiple spaced seeds and multi-index Bloom filters

Alignment-free classification of sequences against collections of sequences has enabled high-throughput processing of sequencing data in many bioinformatics analysis pipelines. Originally hash-table based, much work has been done to improve and reduce the memory requirement of indexing of k-mer sequences with probabilistic indexing strategies. These efforts have led to lower memory highly efficient indexes, but often lack sensitivity in the face of sequencing errors or polymorphism because they are k-mer based. To address this, we designed a new memory efficient data structure that can tolerate mismatches using multiple spaced seeds, called a multi-index Bloom Filter. Implemented as part of BioBloom Tools, we demonstrate our algorithm in two applications, read binning for targeted assembly and taxonomic read assignment. Our tool shows a higher sensitivity and specificity for read-binning than BWA MEM at an order of magnitude less time. For taxonomic classification, we show higher sensitivity than CLARK-S at an order of magnitude less time while using half the memory.

bioinformatics↗