Biology subjects

Liu, Z.-Y.

Publications and source records attributed to Liu, Z.-Y..

11 recordsLinked to original sources

bioRxiv2026

Novel conserved RNA structural motifs regulate genome cyclization of yellow fever virus

The long-range RNA-RNA interaction between the termini of a flavivirus genome is controlled by multiple local RNA secondary and tertiary structures. However, a complete picture of this essential genome cyclization process is still elusive. Herein, by using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE), SHAPE and mutational profiling, in vitro RNA binding assays, and reverse genetics approaches, we demonstrated that the hairpin 2 in the capsid-coding region (cHP2) is required for efficient replication of yellow fever virus and functionally interacts with the 3'-small hairpin (sHP) during genome cyclization. Interestingly, through a combination of multidimensional chemical probing and functional characterization assays, it was discovered that the sHP forms previously unknown tertiary interactions with an immediately upstream GACG region embedded within the 3'-cyclization sequence. This crucial tertiary RNA motif accounts for a potential negative regulatory mechanism of genome cyclization and is universally conserved among the mosquito-borne-related flaviviruses, which constitute a major phylogenetic branch within the subgenus Euflavivirus, genus Orthoflavivirus. Our study highlights the intricacy of RNA-based regulation in flaviviruses.

biochemistry↗

bioRxiv2026

Modeling human embryonic adrenogenesis in pluripotentstem cell-derived corticomedullar-like assembloids

During embryogenesis, the cortical and medullary compartments of the adrenal gland emerge from two distinct sources: intermediate mesoderm-derived steroidogenic progenitors that comprise the cortex, and migratory neural crest-derived catecholaminergic progenitors that give rise to the medulla. The distinct cellular origins and paracrine signaling environments that foster induction, differentiation, and/or migration of cortical and medullary layers present challenges to recapitulating their co-emergence and incorporation in a human pluripotent stem cell (hPSC) based system. To address this, we developed an approach for modeling the adreno-gonadal primordium (AGP) in compound organoids that are organized along a gradient of NR5A1 expression and which unexpectedly incorporate SOX10-expressing Schwann cell precursors that ultimately generate chromaffin cells. Deconstruction of paracrine signaling within AGP-like organoids (AGPLOs) identified a fibroblast growth factor 9 (FGF9)-driven mechanism that expands bridge cell-like chromaffin progenitors and correlates to paracrine signaling cues encountered by physiological correlates along their migration corridor to the cortex in vivo. Combination of NR5A1-expressing cells with chromaffin cell clusters generated corticomedullar-like assembloids (CMLAs) that generated steroids and catecholamines and were responsive to adrenocorticotropic hormone. This work establishes a platform for modeling the reciprocal signaling relationships that drive adrenal gland development and function in health and disease and provides an approach for generating hPSC-derived adrenal cells/tissues that can be applied therapeutically.

developmental biology↗

bioRxiv2025

GeneCAD: Plant Genome Annotation with a DNA Foundation Model

Accurate genome annotation is fundamental to biological discovery, yet identifying gene structures directly from DNA sequence remains a major challenge in complex genomes. We introduce GeneCAD, a sequence-only framework that predicts biologically coherent gene models without requiring species-matched transcriptomic or proteomic evidence. GeneCAD integrates lineage-specific DNA representations from the PlantCAD2 foundation model with a transformer encoder and a chromosome-scale conditional random field (CRF) to enforce structural constraints, such as splice-phase and feature order. To ensure high-quality supervision, we implement a curation strategy using a sequence-based masked-motif score to filter reference transcripts. As a primary validation across diverse angiosperms, including a complex allotetraploid, GeneCAD improves transcript F1 by approximately 9% over current tools like Helixer and BRAKER3, while sharpening boundary precision and achieving a best-in-class recovery of 86% of classical coding sequences. Furthermore, we demonstrate the frameworks modularity by adapting it to animal lineages through the substitution of the underlying DNA foundation model. While the long introns of vertebrates challenge full transcript reconstruction, the model remains highly effective at identifying individual exons. By connecting evolutionary signals with structured decoding, GeneCAD provides a versatile and scalable solution for high-fidelity genome annotation across the Tree of Life. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/685877v3_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@5dd348org.highwire.dtl.DTLVardef@1da37daorg.highwire.dtl.DTLVardef@188ef17org.highwire.dtl.DTLVardef@108da0c_HPS_FORMAT_FIGEXP M_FIG C_FIG Lay SummaryIdentifying where genes are located within a genome is a major challenge in biology, especially in plants with large and repetitive DNA. Current methods often rely on expensive laboratory data or struggle to find genes in "noisy" regions. We developed GeneCAD, a deep-learning tool that identifies genes using only the raw DNA sequence. By using AI models that recognize patterns shaped by millions of years of evolution, GeneCAD predicts gene structures with high accuracy and consistency. Our tests show that GeneCAD outperforms existing tools in plants and can be easily adapted for use in other species, including animals. By removing the need for costly lab experiments, GeneCAD provides an affordable way for researchers to quickly map the genomes of everything from rare wild plants to essential food crops.

bioinformatics↗

bioRxiv2025

PlantCAD2: A Long-Context DNA Language Model for Cross-Species Functional Annotation in Angiosperms

Understanding how DNA sequence encodes biological function remains a fundamental challenge in biology. Flowering plants (angiosperms), the dominant terrestrial clade, exhibit maximal biochemical complexity, extraordinary species diversity (over 100,000 species), relatively recent origins ([~]160 million years), [~]200-fold variation in genome size and relative compact coding regions compared with other eukaryotes. These features present both a unique challenge and opportunity for pre-training DNA language models to understand plant-specific evolutionary conservation, regulatory architectures and genomic functions. Here, we introduce PlantCAD2, an extended context, plant-specific DNA language model with single-nucleotide resolution, pre-trained on 65 angiosperm genomes, together with a series of public benchmarks for evaluation. Comprehensive zero-shot testing shows that PlantCAD2 (676 million parameters) efficiently captures evolutionary conservation, surpassing the 7-billion-parameter Evo2 model in 10 of 12 tasks. With parameter-efficient fine-tuning, PlantCAD2 also outperforms the 1-billion-parameter AgroNT across seven cross-species tasks including chromatin accessible region, gene expression and protein translation. Moreover, its 8,192bp context window substantially improves accessible chromatin prediction in large genomes such as maize (AUPRC increasing from 0.587 to 0.711), underscoring the importance of long-range context for modeling distal regulation. Together, these results establish PlantCAD2 as a powerful, efficient, and versatile foundation model for plant genomics, enabling accurate genome annotation across diverse species.

bioinformatics↗

bioRxiv2025

Extensive genome evolution distinguishes maize within a stable tribe of grasses

Over the last 20 million years, the Andropogoneae tribe of grasses has evolved to dominate 17% of global land area. Domestication of these grasses in the last 10,000 years has yielded our most productive crops, including maize, sugarcane, and sorghum. The majority of Andropogoneae species, including maize, show a history of polyploidy - a condition that, while offering the evolutionary advantage of multiple gene copies, poses challenges to basic cellular processes, gene expression, and epigenetic regulation. Genomic studies of polyploidy have been limited by sparse sampling of taxa in groups with multiple polyploidy events. Here, we present 33 genome assemblies from 27 species, including chromosome-scale assemblies of maize relatives Zea and Tripsacum. In maize, the after-effects of polyploidy have been widely studied, showing reduced chromosome number, biased fractionation of duplicate genes, and transposable element (TE) expansions. While we observe these patterns within the genus Zea, 12 other polyploidy events deviate significantly. Those tetraploids and hexaploids retain elevated chromosome number, maintain nearly complete complements of duplicate genes, and have only stochastic TE amplifications. These genomes reveal variable outcomes of polyploidy, challenging simple predictions and providing a foundation for understanding its evolutionary implications in an ecologically and economically important clade.

evolutionary biology↗

bioRxiv2024

Endogenous FGFs drive ERK-dependent cell fate patterning in 2D human gastruloids

The role of FGF is the least understood of the morphogens driving mammalian gastrulation. Here we investigated the function of FGF in a stem cell model for human gastrulation known as a 2D gastruloid. We found a ring of FGF-dependent ERK activity that closely follows the emergence of primitive streak (PS)-like cells but expands further inward. We showed that this ERK activity pattern is required for PS-like differentiation and that loss of PS-like cells upon FGF receptor inhibition can be rescued by directly activating ERK. We further demonstrated that the ERK-ring depends on localized activation of basolaterally positioned FGF receptors (FGFR) by endogenous FGF gradients. We confirmed and extended previous studies in analyzing expression of FGF pathway components, showing FGFR1 is the main receptor, FGF2 is highly expressed across several cell types, and FGF4/17 are the main FGF ligands expressed in the PS-like cells, similar to the human and monkey embryo but different from the mouse. We found that knockdown of FGF4 greatly reduced PS-like differentiation while FGF17 knockdown primarily affected subsequent mesoderm differentiation. FGF8 expression was spatially displaced from PS-markers and FGF4 expression and peaked earlier, while knockdown led to an expansion in PS-like cells, suggesting FGF8 may counteract FGF4 to limit PS-like differentiation. Thus, we have identified a previously unknown role for FGF-dependent ERK signaling in 2D gastruloids and possibly the human embryo, driven by a mechanism where FGF4 and FGF17 signal through basally localized FGFR1 to induce PS-like cells and their derivatives, potentially restricted by FGF8.

developmental biology↗

bioRxiv2024

Cross-species plant genomes modeling at single nucleotide resolution using a pre-trained DNA language model

Interpreting function and fitness effects in diverse plant genomes requires transferable models. Language models (LMs) pre-trained on large-scale biological sequences can learn evolutionary conservation and offer cross-species prediction better than supervised models through fine-tuning limited labeled data. We introduce PlantCaduceus, a plant DNA LM based on the Caduceus and Mamba architectures, pre-trained on a curated dataset of 16 Angiosperm genomes. Fine-tuning PlantCaduceus on limited labeled Arabidopsis data for four tasks, including predicting translation initiation/termination sites and splice donor and acceptor sites, demonstrated high transferability to 160 million year diverged maize, outperforming the best existing DNA LM by 1.45 to 7.23-fold. PlantCaduceus is competitive to state-of-the-art protein LMs in terms of deleterious mutation identification, and is threefold better than PhyloP. Additionally, PlantCaduceus successfully identifies well-known causal variants in both Arabidopsis and maize. Overall, PlantCaduceus is a versatile DNA LM that can accelerate plant genomics and crop breeding applications.

bioinformatics↗

bioRxiv2023

Pesticide-induced resurgence of the brown planthopper is mediated by diverse actors that promote juvenile hormone biosynthesis and female fecundity

Pesticide-induced resurgence, increases in pest insect populations following pesticide application, is a serious threat to the sustainable control of many highly damaging crop pests. Resurgence can result from pesticide-enhanced pest reproduction, however, the molecular mechanisms mediating this process remain unresolved. Here we show that brown planthopper (BPH) resurgence in rice crops following exposure to sublethal doses of the pesticide emamectin benzoate (EB) results from the coordinated action of a suite of genes that regulate juvenile hormone (JH) levels, resulting in increased JH titer in adult females and enhanced fecundity. We demonstrate that EB treatment at sublethal levels results in profound changes in female BPH fitness including increased egg maturation and oviposition. This enhanced reproductive fitness results from the EB-mediated upregulation of key genes involved in the regulation of JH, including JHAMT and Kr-h1 and the downregulation of allatostatin (AstA) and allatostatin receptor (AstAR) expression. AstA signaling is known to inhibit the production of JH in the corpora allata and hence EB exposure diminishes this inhibitory action. We find that the changes in gene expression following EB exposure are caused by the allosteric action of this insecticide on its molecular target, the glutamate-gated chloride channel (GluCl). Collectively, these results provide mechanistic insights into the regulation of negative pesticide-induced responses in insects and reveal some key actors involved in the JH-signaling pathway that underpin pesticide resurgence. SignificancePesticides remain a key means of controlling many of the worlds insect pests. However, in some cases, pesticide applications can result in resurgence of pest populations due to pesticide-induced increases in fecundity. In the current study, we show that pesticide resurgence in the brown planthopper (BPH) following exposure to the insecticide emamectin benzoate (EB) results from the transcriptional reprogramming of a diverse suite of positive and negative regulators of juvenile hormone (JH), a critical regulator of insect development and reproduction. This in turn leads to profound increases in female BPH reproductive fitness and enhanced fecundity. Our findings unravel some of the molecular mechanisms mediating pesticide-induced pest resurgence and inform the development of novel strategies to control highly damaging crop pests.

ecology↗

bioRxiv2022

Specific Pupylation as IDEntity Reporter (SPIDER) for the identification of Protein-Biomolecule interactions

Protein-biomolecule interactions play pivotal roles in almost all biological processes, the identification of the interacting protein is essential. By combining a substrate-based proximity labelling activity from the pupylation pathway of Mycobacterium tuberculosis, and the streptavidin (SA)-biotin system, we developed Specific Pupylation as IDEntity Reporter (SPIDER) for identifying protein-biomolecular interactions. As a proof of principle, SPIDER was successfully applied for global identification of interacting proteins, including substrates for enzyme (CobB), the readers of m6A, the protein interactome of mRNA, and the target proteins of drug (lenalidomide). In addition, by SPIDER, we identified SARS-CoV-2 Omicron variant specific receptors on cell membrane and performed in-depth analysis for one candidate, Protein-g. These potential receptors could explain the differences between the Omicron variant and the Prototype strain, and further serve as target for combating the Omicron variant. Overall, we provide a robust technology which is applicable for a wide-range of protein-biomolecular interaction studies.

systems biology↗

bioRxiv2020

Genome assembly and annotation of Macadamia tetraphylla

Macadamia is a kind of evergreen nut trees which belong to the Proteaceae family. The two commercial macadamia species, Macadamia integrifolia and M. tetraphylla, are highly prized for their edible kernels. Catherine et al. reported M. integrifolia genome using NGS sequencing technology. However, the lack of a high-quality assembly for M. tetraphylla hinders the progress in biological research and breeding program. In this study, we report a high-quality genome sequence of M. tetraphylla using the Oxford Nanopore Technologies (ONT) technology. We generated an assembly of 750.54 Mb with a contig N50 length of 1.18 Mb, which is close to the size estimated by flow cytometry and k-mer analysis. Repetitive sequence represent 58.57% of the genome sequence, which is strikingly higher compared with M. integrifolia. A total of 31,571 protein-coding genes were annotated with an average length of 6,055 bp, of which 92.59% were functionally annotated. The genome sequence of M. tetraphylla will provide novel insights into the breeding of novel strains and genetic improvement of agronomic traits.

genomics↗

bioRxiv2020

Human Influenza A Virus H1N1pdm Full-length Genome Sequencing in USA and Taiwan in 2015-16 Flu Season and Disease Correlation

During the 2015-16 winter, the US experienced a relatively mild influenza season compared to Taiwan which had a higher number of total and severe cases. While H1N1pdm viruses dominated global surveillance efforts that season, the global distribution of genetic variants and their contributions to disease severity have not been investigated. Samples collected from influenza A positive patients by the Johns Hopkins Center of Excellence for Influenza Research and Surveillance (JH-CEIRS) active surveillance in the emergency rooms in Baltimore, Maryland, USA and northern Taiwan between November 2015 and April 2016, were processed for influenza A virus whole genome sequencing. In Baltimore, the majority of the viruses were the H1N1pdm clade 6B.1 and no H1N1pdm clade 6B.2 viruses were detected. In northern Taiwan, more than half of the H1N1pdm viruses were clade 6B.1 and 38% were clade 6B.2, consistent with the global observation that most 6B.2 viruses circulated in Asia and not North America. Whole virus genome sequence analysis identified two genetic subgroups present in each of the 6B.1 and 6B.2 clades and one 6B.1 intraclade reassortant virus. Clinical data showed 6B.2 patients had more disease symptoms including higher crude and inverse probability weighted odds of pneumonia than 6B.1 patients, suggesting 6B.2 circulation may contribute to the severe flu season in Taiwan. Local surveillance efforts linking H1N1pdm virus sequences to patient clinical and demographic data improve our understanding of influenza circulation and disease potential.

microbiology↗