Biology subjects

Xu, X.

Publications and source records attributed to Xu, X..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

Test-retest reliability of resting-state EEG intrinsic neural timescales

Intrinsic neural timescales (INTs), which reflect the duration of neural information storage within local brain regions and capacity for information integration, are typically measured using autocorrelation windows (ACWs). Extraction of INTs from resting-state brain activity has been extensively applied in psychiatric disease research. Given the potential of INTs as a neural marker for psychiatric disorders, investigating their reliability is crucial. This study, using an open-source database, aimed to evaluate the test-retest reliability of ACW-0 and ACW-50 under both eyes-open and eyes-closed conditions across three sessions. The intraclass correlation coefficients (ICCs) were employed to quantify the reliability of the INTs. Our results showed that INTs exhibited good reliability (ICC > 0.6) at the whole-brain level across different index types and eye states. Spatially, except for the right temporal region in the eyes-open condition, all other regions showed moderate-to-high ICCs. Over 60% of the electrodes demonstrated moderate-to-high INT ICCs under both eyes-open and eyes-closed conditions, with ACW-0 being more stable than ACW-50. This present study comprehensively assessed the reliability of INT under various conditions, providing robust evidence for their stability in neuroscience and psychiatry.

neuroscience↗

bioRxiv2024

A near-complete genome assembly of the bearded dragon Pogona vitticeps provides insights into the origin of Pogona sex chromosomes

BackgroundThe agamid dragon lizard Pogona vitticeps is one of the most popular domesticated reptiles to be kept as pets worldwide. The capacity of breeding in captivity also makes it emerging as a model species for a range of scientific research, especially for the studies of sex chromosome origin and sex determination mechanisms. ResultsBy leveraging the CycloneSEQ and DNBSEQ sequencing technologies, we conducted whole genome and long-range sequencing for a captive-bred ZZ male to construct a chromosome-scale reference genome for P. vitticeps. The new reference genome is [~]1.8 Gb in length, with a contig N50 of 202.5 Mb and all contigs anchored onto 16 chromosomes. Genome annotation assisted by long-read RNA sequencing greatly expanded the P. vitticeps lncRNA catalog. With the chromosome-scale genome, we were able to characterize the whole Z sex chromosome for the first time. We found that over 80% of the Z chromosome remains as pseudo-autosomal region (PAR) where recombination is not suppressed. The sexually differentiated region (SDR) is small and occupied mostly by transposons, yet it aggregates genes involved in male development, such as AMH, AMHR2 and BMPR1A. Finally, by tracking the evolutionary origin and developmental expression of the SDR genes, we proposed a model for the origin of P. vitticeps sex chromosomes which considered the Z-linked AMH as the master sex-determining gene. ConclusionsOur study provides novel insights into the sex chromosome origin and sex determination of this model lizard. The near-complete P. vitticeps reference genome will also benefit future study of amniote evolution and may facilitate genome-assisted breeding.

genomics↗

bioRxiv2024

Deciphering the Cell Specific Transcript Heterogeneity and Alternative Splicing during the Early Embryonic Development of Zebrafish

Cell fate determination during early embryonic development is a complex process modulated by gene expression. The intricate interplay of transcriptional and post-transcriptional regulation is integral to the developmental trajectory of embryogenesis, yet how RNA processing may contribute to early development programming is largely elusive. Leveraging recent technological advances in single-molecule nanopore sequencing, we developed a single-cell long-read transcriptome sequencing technology, allowing a clear view of transcript diversity during zebrafish embryogenesis during pre- and post-zygotic genome activation (ZGA). A closer examination of the dynamic transcript usage and potential alternative splicing revealed that abundant stage-specific transcripts with differential coding potentials are involved in distinct biological functions. Specifically, we identified two cell populations at the onset of ZGA based on isoform diversity instead of gene profiling, which followed divergent developmental trajectories toward the ectoderm and the presumptive ectoderm. These two populations of cells were characterized by divergent splicing regulations linked to differential RNA-binding proteins, including SNRPA and SFPQ. Altogether, using the single-cell long-read transcriptome sequencing strategy, we work has revealed the cell-specific transcriptome dynamics contributing to the cell fate determination during embryogenesis.

developmental biology↗

bioRxiv2024

Telomere-to-telomere African wild rice (Oryza longistaminata) reference genome reveals segmental and structural variation

Rice (Oryza sativa) is one of the most important staple food crops worldwide, and its wild relatives serve as an important gene pool in its breeding. Compared with cultivated rice species, African wild rice (Oryza longistaminata) has several advantageous traits, such as resistance to increased biomass production, clonal propagation via rhizomes, and biotic stresses. However, previous O. longistaminata genome assemblies have been hampered by gaps and incompleteness, restricting detailed investigations into their genomes. To streamline breeding endeavors and facilitate functional genomics studies, we generated a 343-Mb telomere-to-telomere (T2T) genome assembly for this species, covering all telomeres and centromeres across the 12 chromosomes. This newly assembled genome has markedly improved over previous versions. Comparative analysis revealed a high degree of synteny with previously published genomes. A large number of structural variations were identified between the O. longistaminata and O. sativa. A total of 2,466 segmentally duplicated genes were identified and enriched in cellular amino acid metabolic processes. We detected a slight expansion of some subfamilies of resistance genes and transcription factors. This newly assembled T2T genome of O. longistaminata provides a valuable resource for the exploration and exploitation of beneficial alleles present in wild relative species of cultivated rice.

genomics↗

bioRxiv2024

Efficiently Constructing Complete Genomes with CycloneSEQ to Fill Gaps in Bacterial Draft Assemblies

BackgroundCurrent microbial sequencing relies on short-read platforms like Illumina and DNBSEQ, favored for their low cost and high accuracy. However, these methods often produce fragmented draft genomes, hindering comprehensive bacterial function analysis. CycloneSEQ, a novel long-read sequencing platform developed by BGI-Research, its sequencing performance and assembly improvements has been evaluated. FindingsUsing CycloneSEQ long-read sequencing, the type strain produced long reads with an average length of 11.6 kbp and an average quality score of 14.4. After hybrid assembly with short reads data, the assembled genome exhibited an error rate of only 0.04 mismatches and 0.08 indels per 100 kbp compared to the reference genome. This method was validated across 9 diverse species, successfully assembling complete circular genomes. Hybrid assembly significantly enhances genome completeness by using long reads to fill gaps and accurately assemble multi-copy rRNA genes, which unable be achieved by short reads solely. Through data subsampling, we found that over 500 Mbp of short-read data combined with 100 Mbp of long-read data can result in a high-quality circular assembly. Additionally, using CycloneSEQ long reads effectively improves the assembly of circular complete genomes from mixed microbial communities. ConclusionsCycloneSEQs read length is sufficient for circular bacterial genomes, but its base quality needs improvement. Integrating DNBSEQ short reads improved accuracy, resulting in complete and accurate assemblies. This efficient approach can be widely applied in microbial sequencing.

genomics↗

bioRxiv2024

The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG[~]MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation. Significance statementMITF is critically involved in melanoma progression and phenotype switching. We discovered that MAFG interacts with MITF to influence expression of MITF target genes and facilitate a shift toward a dedifferentiated melanoma cell state. This study demonstrates that MAFG promotes melanomagenesis by influencing MITF activity, an unappreciated mechanism of MITF regulation.

cancer biology↗

bioRxiv2024

Crystal structure and catalytic mechanism of PL35 family glycosaminoglycan lyases with an ultrabroad substrate spectrum

Recently, a new class of glycosaminoglycan (GAG) lyases (GAGases) belonging to PL35 family has been discovered with an ultrabroad substrate spectrum that can degrade three types of uronic acid-containing GAGs (hyaluronic acid, chondroitin sulfate and heparan sulfate) or even alginate. In this study, the structures of GAGase II from Spirosoma fluviale and GAGase VII from Bacteroides intestinalis DSM 17393 were determined at 1.9 and 2.4 [A] resolution, respectively, and their catalytic mechanism was investigated by the site-directed mutant of their crucial residues and molecular docking assay. Structural analysis showed that GAGase II and GAGase VII consist of an N-terminal (/)6 toroid multidomain and a C-terminal two-layered {beta}-sheet domain with Mn2+. Notably, although GAGases share similar folds and catalytic mechanisms with some GAG lyases and alginate lyases, they exhibit higher structural similarity with alginate lyases than GAG lyases, which may present a crucial structural evidence for the speculation that GAG lyases with (/)n toroid and antiparallel {beta}-sheet structures arrived by a divergent evolution from alginate lyases with the same folds. Overall, this study not only solved the structure of PL35 GAG lyases for the first time and investigated their catalytic mechanism, especially the reason why GAGase III can additionally degrade alginate, but also provided a key clue in the divergent evolution of GAG lyases that originated from alginate lyases.

biochemistry↗

bioRxiv2024

A convenient single-cell newly synthesized transcriptome assay reveals gene expression dynamics during early-stage T-cell activation

Sequencing newly synthesized transcriptome alongside regular transcriptome in single cells enables the study of gene expression temporal dynamics during rapid chromatin and gene regulation processes. Existing assays for profiling single-cell newly synthesized transcriptome often require specialized technical expertise to achieve high cellular throughput, limiting their accessibility. Here, we developed NOTE-seq, a method for simultaneous profiling of regular and newly synthesized transcriptomes in single cells with high cellular throughput. NOTE-seq integrates 4-thiouridine labeling of newly synthesized RNA, thiol-alkylation-based chemical conversion, and a streamlined 10X Genomics workflow, making it accessible and convenient for biologists without extensive single-cell expertise. Using NOTE-seq, we investigated the temporal dynamics of gene expression during early-stage T-cell activation, identified transcription factors and regulons in Jurkat and naive T cells, and uncovered the down-regulation of FLI1 as a master transcription factor upon T-cell stimulation. Notably, topoisomerase inhibition led to the depletion of both topoisomerases and FLI1 in T cells through a proteasome-dependent mechanism driven by topoisomerase cleavage complexes, highlighting potential complications topoisomerase-targeting cancer chemotherapies could pose to the immune system.

genomics↗

bioRxiv2024

A single-molecule nanopore sequencing platform

Nanopore sequencing, a third-generation sequencing technology, has revolutionized the gene sequencing industry with its advantages of long reads, fast speed, real-time sequencing and analysis, and potential in detecting base modifications. This technology allows researchers to sequence longer DNA fragments in a single read, providing more comprehensive genomic information compared to previous methods. Nanopore sequencing operates on electrical signals generated by a nanopore embedded in a membrane separating two electrolyte-filled chambers. When single-stranded DNA (ssDNA) passes through the nanopore, it creates variations in the current that correspond to different DNA bases. By analyzing these current fluctuations with machine learning algorithms, the DNA sequence can be determined. In this study, we introduced several improvements to nanopore sequencing, including nanopore local chemistry sequencing, novel motor and pore proteins, chip design, and basecalling algorithms. Our new nanopore sequencing platform, CycloneSEQ, demonstrated long-duration sequencing (107 hours) on a single chip with high yield (>50 Gb). In human genomic DNA sequencing, CycloneSEQ was able to produce long reads with N50 33.6 kb and modal identity 97.0%. Preliminary findings on human whole-genome de novo assembly, variant calling, metagenomics sequencing, and single-cell RNA sequencing have further highlighted CycloneSEQs potential across different areas of genomics.

genomics↗

bioRxiv2024

Three-dimension transcriptomics maps of whole mouse embryo during organogenesis

Understanding mammalian development heavily relies on classical animal models like the house mouse (Mus musculus). Advanced spatial transcriptomics has enabled biologists to break new ground in studies of molecular dynamics and cellular patterning during embryonic development with spatiotemporal resolution. To construct a comprehensive developmental trajectory, current three-dimensional (3D) spatial transcriptomic profiling leverages mouse embryos from gastrulation (E5.5) to organogenesis (E13.5) in continuity. However, a crucial phase for early organogenesis between E9.5 and E11.5 was deficient. To unveil the mystery of this stage, we present the 3D transcriptomics of mouse embryos at E9.5 and E11.5, with a widely applicable reconstruction workflow that bypasses sophisticated bioinformatic calculations. As our 3D atlas is generated at single-cell resolution, we demonstrate how organogenetic processes can be interpreted at different levels of granularity, from local cellular interactions to whole embryonic regionalization. We release the open-access database MOSTA3D (Mouse Organogenesis Spatiotemporal Transcriptomic Atlas in Three-dimensional) and hope a broader community will contribute to extending this framework from conception to senility in the near future.

developmental biology↗

bioRxiv2024

A Novel Computational Machine Learning Pipeline to Quantify Similarities in Three-Dimensional Protein Structures

Animal models are widely used during drug development. The selection of suitable animal model relies on various factors such as target biology, animal resource availability and legacy species. It is imperative that the selected animal species exhibit the highest resemblance to human, in terms of target biology as well as the similarity in the target protein. The current practice to address cross-species protein similarity relies on pair-wise sequence comparison using protein sequences, instead of the biologically relevant 3-dimensional (3D) structure of proteins. We developed a novel quantitative machine learning pipeline using 3D structure-based feature data from the Protein Data Bank, nominal data from UNIPROT and bioactivity data from ChEMBL, all of which were matched for human and animal data. Using the XGBoost regression model, similarity scores between targets were calculated and based on these scores, the best animal species for a target was identified. For real-world application, targets from an alternative source, i.e., AlphaFold, were tested using the model, and the animal species that had the most similar protein to the human counterparts were predicted. These targets were then grouped based on their associated phenotype such that the pipeline could predict an optimal animal species.

pharmacology and toxicology↗

bioRxiv2024

Two TAL effectors of Xanthomonas citri pv. malvacearum target GhSWEET15 as the susceptibility genes for bacterial blight of cotton

Bacterial Blight of Cotton (BBC) caused by Xanthomonas citri pv. malvacearum (Xcm) is an important and destructive disease affecting cotton plants. Transcription activator-like effectors (TALEs) released by the pathogen regulate cotton resistance to the susceptibility. In this study, we sequenced the whole genome of Xcm Xss-V2-18 and identified eight tal genes; seven on the plasmids and one on the chromosome. Deletion and complementation experiments of Xss-V2-18 tal genes demonstrated that Tal1b is required for full virulence on cotton. Transcriptome profiling coupled with TALE-binding element prediction revealed that Tal1b targets GhSWEET15A04/D04 and GhSWEET15D02 simultaneously. Expression analysis confirmed the independent inducibility of GhSWEET15A04/D04 and GhSWEET15D02 by Tal1b, whereas GhSWEET15A04/D04 is additionally targeted by Tal1. Moreover, GUS ({beta}-glucuronidase) and Xa10-mediated HR (hypersensitive response) assays indicated that the EBEs are required for the direct and specific activation of the candidate targets by Tal1 and Ta1b. These findings may advance our understanding of the dynamics between TALEs and EBEs, and decipher a simple and effective DNA-binding mechanism that could lead to the development of more efficient methods for gene editing and transgenic research.

pathology↗

bioRxiv2024

Chronic cigarette smoke exposure masks pathological features of Helicobacter pylori infection while promoting tumor initiation

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1-3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori-infected smokers are at a 2-11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within one week of infection. The mice were exposed to cigarette smoke (CS) five days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared to filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation.

cancer biology↗

bioRxiv2024

Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism

Approximately 40% ER-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ER level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ER at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre+; Frmd8fl/fl; PyMT mice accelerates mammary tumor growth and loss of luminal phenotype, and confers tamoxifen resistance. Single-cell RNA profiling reveals that Frmd8 loss decreases the proportion of hormone-sensing differentiated epithelial cells and downregulates the levels of ER. Mechanically, on one hand, loss of FRMD8 inhibits ESR1 transcription via suppressing the expression of FOXO3A, a transcription factor of ESR1. On the other hand, FRMD8 interacts both with ER and UBE3A, and disrupts the interaction of UBE3A with ER, thereby blocking UBE3A-mediated ER degradation. In breast cancer patients, FRMD8 gene promoter is found hypermethylated and low level of FRMD8 predicts poor prognosis. Therefore, FRMD8 is an important regulator of ER and may control therapeutic sensitivity to tamoxifen in ER-positive breast cancer patients. Impact StatementTumor suppressive protein FRMD8 inhibits breast cancer progression by regulating the level of ER and has the possibility to be a potential target for overcoming tamoxifen treatment resistance.

cancer biology↗

bioRxiv2024

In silico screening by AlphaFold2 program revealed the potential binding partners of nuage-localizing proteins and piRNA-related proteins

Protein-protein interactions are the fundamental features for understanding the molecular functions and regulations of proteins. Despite extensive databases, many interactions remain uncharacterized due to the intensive labor required for experimental validation. In this study, we utilized the AlphaFold2 program to predict interactions among proteins localized in the nuage, a germline-specific non-membrane organelle critical for piRNA biogenesis and RNA regulation. We screened 20 types of nuage proteins for 1:1 interactions and predicted dimer structures. Among those, five pairs represented novel interaction candidates. Three pairs, including Spn-E_Squ, were validated through co-immunoprecipitation in cultured cells and confirmed the interactions. Disruption of the salt bridges at the Spn-E_Squ interface verified their functional importance, underscoring the predictive models accuracy. Our analysis was extended to include interactions between three representative nuage components, Vas, Squ, and Tej, and approximately 430 oogenesis-related proteins. Following this extended analysis, co-immunoprecipitation in S2 cells verified interactions for three pairs: Mei-W68_Squ, CSN3_Squ, and Pka-C1_Tej. Furthermore, the majority of Drosophila proteins, [~]12,000, were screened for the interaction with Piwi protein, a central player in the piRNA pathway. Approximately 1.5% of the pairs, totaling 164 pairs, with a score above 0.6, were identified as potential binding partners. This in silico approach not only efficiently identifies potential interaction partners but also significantly reduces the gap by facilitating the integration of bioinformatics and experimental biology.

molecular biology↗

bioRxiv2024

Reconstitution of chromatin reorganization during mammalian oocyte development

SignificanceThe generation of developmentally competent eggs requires oocyte growth and maturation. When compared to meiotic maturation, relatively little is known about the key processes that happen in growing oocytes. Since the first visualization of oocyte chromatin under the electron microscope, we have known that growing oocytes undergo a fundamental transition from the non-surrounded nucleolus (NSN) to surrounded nucleolus (SN) chromatin configuration. NSN-to-SN transition is crucial for subsequent embryonic development after fertilization, but what drives NSN-to-SN transition during mammalian oocyte development is still unknown. Here we show that natural degradation of RNA polymerase II (RNAPII) by segregase and proteasome drives NSN-to-SN transition, challenging the conventional view that transcriptional silencing and NSN-to-SN transition are driven by independent epigenetic mechanisms in mammalian oocytes. The final step of oocyte growth, which reorganizes chromatin from the uncondensed, non-surrounded nucleolus (NSN) configuration to the condensed, surrounded nucleolus (SN) configuration, is essential for embryonic development after fertilization. However, the mechanism of NSN-to-SN transition remains unknown. Here, we identify RNA polymerase II (RNAPII) degradation as the key driver of this process. RNAPII inhibitors, but not nucleoside-based transcription inhibitors, swiftly induced RNAPII degradation and NSN-to-SN transition in oocytes. Strikingly, induced SN-like nuclei recapitulated epigenetic features, chromatin interactions and developmental potential in SN oocytes. Using segregase and proteasome inhibitors and the newly established scFv miniTrim-Away for nuclear proteins, we further demonstrate that RNAPII degradation is necessary and sufficient for NSN-to-SN transition in mouse and human. RNAPII degradation globally cleared RNAPII from transcriptionally active chromatin and increased chromatin dynamics, concomitantly leading to transcriptional silencing and chromatin rearrangement in oocytes. Our study elucidates the framework of chromatin reorganization in growing mammalian oocytes and provides an alternative source of fully grown oocyte nuclei, representing a milestone for the potential use of growing oocytes in reproductive medicine.

developmental biology↗

bioRxiv2024

Modulation Of SUDEP By Central Serotonergic Cooperating with Noradrenergic Circuits: A Synergistic-Dependent Manner

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Despite previous accumulating evidence has shown that seizure-induced respiratory arrest (S-IRA) may play the main contributor to SUDEP as an initiating event preeminent cause of mortality, the specific underlying mechanism of action remains unclear. Based on our previous work, serotonin (5-HT) signaling in the dorsal raphe nucleus (DRN) is strongly implicated in S-IRA in animal models, including the DBA/1 mice, on the meanwhile, norepinephrine (NE) neurons of the locus coeruleus (LC) also plays a vital role in regulating respiratory function on its own. Superficially, monoaminergic neuron, as important neurotransmitters in the central nervous system, have similar modes of action in the maintenance of nervous system balance, and each of them has a regulatory effect on SUDEP. However, it remains to be investigated whether monoaminergic neuron family (NE and 5-HT) are related in the mechanism of regulating SUDEP, what is even more curious is whether the two are intrinsically linked. Thus, we hypothesize neural mechanism of central noradrenergic and serotonergic circuits in modulating SUDEP in a synergistic-dependent manner, this endeavor will culminate in a significant breakthrough in elucidating the precise mechanism of action underlying SUDEP. In our study, we will use chemogenetics, optogenetics, calcium signal recording, and bidirectional tracing to explore the internal mechanism of DR-LC regulating the occurrence of SUDEP, and by specifically injecting 5-HT2AR antagonist Ketanserin (KET) and/or NE-1R antagonist Prazosin into the pre-Botzinger complex (PBC), it was finally elucidate that the DR-LC-PBC network can effectively reduce the incidence of SIRA. We firstly proposed a powerful target for exploring the reduction of the incidence of SUDEP, which has great clinical translation potential.

neuroscience↗

bioRxiv2024

SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center (GAC), was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitivity to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse (GEM) and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.

cancer biology↗