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Results for “molecular biology”

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bioRxiv2026

Gene duplication of SNAPC1 generates transcription factors for snRNAs and sex-specific piRNAs

Piwi-interacting RNAs (piRNAs) are small non-coding RNAs essential for transposon silencing and germline integrity across metazoans. In many species, piRNA expression is sexually dimorphic, yet the molecular mechanisms underlying this sex specificity remain poorly understood. In Caenorhabditis elegans, sexually dimorphic piRNA expression is regulated at the transcriptional level. We previously identified SNPC-1.3, a paralog of the small nuclear RNA (snRNA) activating protein complex (SNAPc/SNPC) subunit SNAPC1, as a male-specific piRNA transcription factor. However, the factors governing female piRNA expression remained elusive. Here, we identify SNPC-1.2, a second SNPC-1 paralog, as a female-specific piRNA transcription factor. SNPC-1.2 interacts with the core piRNA transcriptional machinery, binds female piRNA loci, is required for female piRNA expression, and promotes hermaphrodite fertility. In contrast, a third paralog, SNPC-1.1, retains the ancestral SNAPc function in snRNA transcription and is dispensable for piRNA biogenesis. Together, these findings reveal how gene duplication and functional specialization within the snpc-1 gene family generate specificity factors that direct the core SNAP complex to distinct genomic targets, providing a molecular mechanism for sexually dimorphic piRNA expression while maintaining canonical snRNA transcription.

molecular biology↗

bioRxiv2026

Invasive mosquito species Aedes aegypti and Aedes albopictus are competent vectors for Barmah Forest Virus

Barmah Forest Virus (BFV), an arthropod-born virus transmitted by mosquitoes, is of significant public health concern in Australia and regions in the Pacific. Recent climate change and globalization raise the potential for BFV to extend its geographic distribution. Despite the rising importance of BFV, its vector dynamics remain poorly understood, particularly concerning the vector competence of different mosquito species. This study aims to investigate the vector competence of BFV across various mosquito species, beyond those endemic to the Australasian region, especially focusing on global relevant vector species. No transmission was observed for Culex quinquefasciatus and Cx. torrentium as well as Anopheles stephensi. In contrast, both investigated Aedes species, Ae. aegypti as well as Ae. albopictus, exhibited BFV-positive saliva across all four temperature profiles (18{degrees}C, 21{degrees}C, 24{degrees}C or 27{degrees}C) examined. These two invasive mosquito species must therefore be classified as potential vectors for BFV, indicating the potential risk of BFV transmission outside of Australia.

molecular biology↗

bioRxiv2026

m1A58 acts as a conformational checkpoint coupling human initiator tRNA maturation to translation initiation

tRNAs are characterized by extensive chemical modifications that influence tRNA fate. N1-methyladenosine at position 58 (m1A58) is a widespread core tRNA modification linked to physiological and pathological processes. However, how m1A58 coordinate tRNA folding and processing to ensure translational efficiency in mammalian cells remains largely unknown. Using acute dTAG-mediated degradation and CRISPR-Cas9 knockout, we identified initiator methionine tRNA (tRNAiMet) as selectively vulnerable to m1A58 loss, lacking the isodecoder buffering observed for most other tRNA isoacceptors. NMR analysis of the tRNAiMet showed that m1A58 stabilizes D/T-loop interactions, consistent with a maturation-competent conformation. In vitro processing assays further demonstrated that m1A58 promotes RNase P-mediated 5'-leader removal and RNase Z-mediated 3'-trailer cleavage, while La/SSB protects accumulated precursors. Disrupting this checkpoint impaired the assembly of the eIF2-containing 43S pre-initiation complex and global protein synthesis, which was substantially rescued by adding m1A58-modified tRNAiMet. Acute TRMT6 degradation elicited temporally coordinated gene-expression responses involving proteostasis, transport and signaling. Together, these findings establish m1A58 as a conformational checkpoint coupling human initiator-tRNA maturation to translation initiation and stress responses.

molecular biology↗

bioRxiv2026

RSV competes with the host for translational machinery without a host shutoff strategy

RNA viruses often enhance ribosome recruitment to their own mRNAs through non-canonical sequence elements or by degrading host mRNA. Respiratory syncytial virus (RSV) produces mRNAs with host-like features, including 5'-cap and poly(A) tail. Therefore, the virus lacks an obvious mechanism to preferentially protect its own mRNAs or recruit ribosomes. Furthermore, it remains unknown how RSV interacts with antiviral defense pathways that would reduce cap-dependent translation. Using spike-in normalized sequencing of total and ribosome-associated RNA, we found that RSV does not appear to evoke any host shutoff mechanisms to limit the expression of host genes. These findings show that RSV manages to make use of available ribosomes by competing effectively with host mRNAs and any translational shutoff mechanism would be detrimental. Consistent with this, we found that following activation of antiviral host pathways that reduce cap-dependent translation, translation of RSV mRNAs is decreased to the same extent as host mRNAs. Furthermore, we found that RSV infection does not trigger the dsRNA-activated kinase PKR (which initiates the ISR) and OAS (activates endonuclease RNase L) pathways. These data support a model in which RSV achieves viral protein production, not though inhibiting the host, but by successfully competing with host mRNAs and avoiding activation of antiviral pathways.

molecular biology↗

bioRxiv2026

Design and Validation of New Primers for Specific and Sensitive Real-time PCR Detection and Quantification of Seven Botulinum Encoding Genes (Serotype A-G) of Clostridium botulinum

Botulinum neurotoxins (BoNTs) comprise a highly diverse group of seven serotypes (from A-G) and over 40 subtypes worldwide. Previous primer- and probe-based nucleic acid amplification tests (NAATs) for detection of BoNT encoding genes are challenged by high levels of nucleotide polymorphism both across and within subtypes. In this study, multiple BoNT gene sequences were aligned to identify highly conserved regions for the design of new primers that enable the detection of all seven serotypes under the same conditions. Specific primer sets were designed and validated using in silico, conventional and real-time PCR with constructed plasmids carrying the target fragments and spiked food matrices. The established procedure achieved highly specific and sensitive detection of BoNT serotypes A-G with sensitivity of 10 copies/reaction and a total turnaround time of approximately 1.5 hours. The procedure also eliminated the carryover PCR product by using uracil-N-glycosylase in combination with dUTP in the assay reaction mix. This study provides an alternative NAAT with higher coverage and compliments the traditional mouse bioassays in enhancing global botulism surveillance capabilities.

molecular biology↗

bioRxiv2026

A Metabolic Labeling Strategy for Tracking Protein Synthesis in Complex Biological Systems

Protein synthesis supports most biological processes. In the brain in particular, protein synthesis plays a critical role in physiological and pathological states. Here, we describe Tellurophene-Alkyne Cycloaddition-mediated Amino acid Tagging (TeACAT), a versatile strategy for fast, facile, and flexible tagging of newly synthesized proteins in mice. TeACAT is based on metabolic incorporation of the non-canonical amino acid TePhe into proteins by the endogenous protein synthesis machinery. Due to their high similarity, TePhe can efficiently replace canonical Phe without dietary or genetic manipulation. The subsequent bio-orthogonal reaction of TePhe with either fluorescent dyes or affinity handles enables both visualization and affinity enrichment of proteins synthesized during TePhe exposure. TeACAT is compatible with immunofluorescence for cell-type specific visualization of protein synthesis with subcellular resolution and can be used in conjunction with routine proteomics to identify and quantify newly synthesized proteins. Robust incorporation into the mouse proteome was observed on the scale of hours to days, allowing the interrogation of various biological processes. In summary, TeACAT enables the visualization and quantification of protein synthesis with minimal perturbation for biological discoveries.

molecular biology↗

bioRxiv2026

Structural basis for catalytic and inhibitory divergence between archaeal and bacterial ammonia monooxygenases

Ammonia oxidation initiates nitrification and is closely linked to microbial N2O production. Ammonia monooxygenase (AMO) catalyzes the first and rate-limiting step of nitrification and is widespread across evolutionarily distinct ammonia-oxidizing archaea (AOA) and bacteria (AOB). The ocean is the largest biome for AOA and AOB, which have distinct ecological niches and markedly different sensitivities to nitrification inhibitors. However, the lack of archaeal AMO structures and inhibitor-bound AMO complexes has hindered mechanistic understanding of the architectural, catalytic, and inhibitory divergence between these two enzyme systems. Here, we report high-resolution cryo-electron microscopy (cryo-EM) structures of marine archaeal AMO captured in active and inactivated states within its native membrane environment, together with inhibitor-bound structures of estuarine bacterial AMO. Archaeal AMO forms an unexpected cup-shaped homotrimer composed of eight subunits per protomer and exhibits substantial architectural divergence from bacterial AMO. Integrated structural, biochemical, kinetic, and computational analyses reveal distinct periplasmic architectures, copper-center organization, and hydrophobic channels between archaeal and bacterial AMOs for ammonium acquisition, catalysis and inhibitor response. These findings provide a structural and mechanistic framework for understanding how archaeal and bacterial AMOs have diverged to distinct ammonia-oxidizing strategies and inhibitor susceptibilities across environmentally important ammonia oxidizers.

molecular biology↗

bioRxiv2026

The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres

Cancers maintain their telomeres through two telomere maintenance mechanisms: 85-90% of cancers rely on telomerase (TEL+), while 10-15% of cancers adopt the Alternative Lengthening of Telomeres (ALT) pathway. The Break-Induced Replication (BIR) pathway plays a critical role in maintaining telomere length in the ALT+ cells. In both yeast and human, PIF1, a 5' to 3' helicase, is required for the robust activity of BIR. However, the extent of human PIF1 (hPIF1) involvement in the ALT pathway remains unknown. Here we showed that hPIF1 can be recruited to damaged telomeres in ALT+ cells. In addition, we demonstrated that inhibition of hPIF1 induced DNA damage and G quadruplex (G4) accumulation at ALT telomeres, leading to a moderate reduction of the mean telomere length. Most interestingly, we demonstrated that inhibition of hPIF1 also attenuates checkpoint activation, BLM recruitment, single-stranded DNA (ssDNA) formation, DNA damage, and G4s at telomeres in the FANCM deficient ALT+ cells. Finally, we showed that inactivation of hPIF1 affects the viability of both ALT+ and TEL+ cancers, suggesting that hPIF1 is a potential drug target for cancer therapy.

molecular biology↗

bioRxiv2026

Elucidating the functional domain architecture of ArCS1, a biomineralizing myosin chitin synthase: I. The role of lipids

In molluscs, chitin synthases are essential for biologically controlled biomineralization, with some variants possessing a myosin motor domain that may link polymer synthesis to the cytoskeleton. Experimentally, we established a reliable workflow for expressing ArCS1_E22TM in Dictyostelium discoideum and developed effective purification methods to reconstitute ArCS1_E22TM in nanodiscs using MSPs and specific lipid composition. MSP1D1deltaH5 proved optimal for nanodisc formation, yielding homogeneous, monodisperse discs (~8.2 nm). Lipids were refined to POPC:POPE:POPG (3:1:1) with 20% cholesterol, improving nanodisc quality and uniformity as observed by negative-stain EM. The full-length ArCS1 and its subdomains were modeled using AlphaFold3; the myosin motor, glycosyltransferase, and transmembrane regions are well-defined internally but loosely constrained relative to one another, suggesting flexible linking and conformational coupling. Modelling with Mg2+ and oleic acid as ligands and comparative analyses with bacterial cellulose synthase and yeast chitin synthase 1 provided insights into substrate binding and a potential mechanism for chitin polymerization and translocation. This research establishes a standard procedure for comprehensive structural analyses of recombinant molluscan chitin synthase in near-native or biomimetic membranes. This sets the stage for high-resolution cryo-electron microscopy to determine the first experimentally resolved structure of a molluscan chitin synthase and to provide insight into the enzyme's architecture and the regulatory mechanisms of biomineralization.

molecular biology↗

bioRxiv2026

Half-match recombination drives bridge RNA-guided excision and off-target insertion

IS110-family bridge recombinases are a recently identified class of compact, RNA-guided editors in which a bridge RNA (bRNA) directs the recombination of a donor DNA into a target site. In the current model, the bRNA engages fully complementary donor and target sequences within a single synaptic complex to drive double-stranded recombination, implying that the transposon is cut from its donor site rather than copied, yet neither the strandedness of the excised intermediate nor the requirement for full complementarity has been tested directly. Here we reconstituted IS621 recombination in a cell-free transcription-translation system, building representative arrangements of the excision and insertion reactions and characterizing the outcomes. We find that IS621 predominantly excises a single strand, releasing a single-stranded circle and leaving the donor site intact, consistent with copy-and-paste transposition. By introducing mismatches into the bRNA target sequences, we further find that excision proceeds independently of target-site complementarity, relying strictly on donor-arm recognition; we term this "half-match" recombination, because a substrate matching only half of the bRNA is sufficient. We also find half-match activity during insertion, both in vitro and in a published genome-editing experiment, where it accounts for approximately half of non-target insertion reads. Half-match recombination provides both a mechanistic explanation for off-target insertion and a framework for the rational design of high-fidelity bridge recombinases.

molecular biology↗

bioRxiv2026

Phosphorylation of spleen tyrosine kinase Y130 positively regulates intracellular signaling and functional responses in platelets

Syk is a non-receptor type protein-tyrosine kinase (PTK), which is associated with platelets surface receptors, glycoprotein VI (GPVI) and C-type lectin-like receptor II-type (CLEC-2). Syk is also expressed in most hematopoietic lineage cells and other cells, such as fibroblasts and neuronal cells. Syk has two tandem SH2 motifs and a C-terminal kinase domain, which are interrupted by interdomains A and B containing multiple tyrosine residues playing a regulatory role upon phosphorylation. This study aims to evaluate the role of Y130 in Syk signaling in platelets. Syk(Y130F) knock-in (KI) mice we generated using the CRISPR-Cas9 technique represent the first in-vivo model harboring this mutation. Using this system, we compared the platelet signaling and responses in wild-type (WT) and Syk(Y130F) littermates. Platelets from homozygous Syk(Y130F) mice showed a decrease in functional responses after activation with CRP, a GPVI agonist, and CLEC-2 crosslinking compared to WT littermates with no significant differences in responses to PAR-4 or purinergic receptor agonists. Key signaling events triggered via both GPVI and CLEC-2, including phosphorylation LAT and PLC-2, were also reduced in Syk(Y130F) platelets at low agonist concentrations. Consistent with these findings, the time to occlusion in the FeCl3 injury model and bleeding time in the tail bleeding assay were significantly enhanced in Syk(Y130F) mice compared to WT littermates. Thus, phosphorylation of Syk Y130 enhances GPVI- and CLEC-2-mediated signaling and functional responses in platelets affecting thrombosis and hemostasis.

molecular biology↗

bioRxiv2026

Inheritance of a Single Edited CD46 Allele Is Associated with Reduced Ex Vivo Susceptibility to Bovine Viral Diarrhea Virus

Bovine viral diarrhea virus (BVDV) remains an economically important pathogen of cattle despite widespread vaccination. A homozygous CD46-edited Gir heifer (Ginger) was previously shown to have significantly reduced susceptibility to BVDV. The edited allele contains an in-frame six amino acid substitution within the virus-binding domain of the BVDV entry receptor CD46, replacing residues G82QVLAL with A82LPTFS. Here, we investigated whether reduced BVDV susceptibility is maintained when the edited allele is inherited in the heterozygous state. Ginger was artificially inseminated with semen from an unedited Gir bull and produced a healthy heterozygous CD46-edited bull calf (Giraldo). Whole-genome sequencing confirmed the inheritance and structural integrity of Giraldo's edited allele. Compared with Ginger, Giraldo exhibited similarly reduced ex vivo BVDV susceptibility across primary fibroblasts, lymphocytes, and monocytes, despite inheriting a wild-type CD46 allele from the sire. Allele-specific CD46 RNA expression analysis demonstrated expression of both the edited and wild-type CD46 alleles. Thus, the reduced-susceptibility phenotype was not attributable to transcriptional silencing of the wild-type allele. Lentiviral complementation studies in CD46-knockout Madin-Darby bovine kidney (MDBK) cells further demonstrated that this wild-type CD46 allele was competent to support BVDV infection when expressed independently. Together, these findings indicate that the CD46 A82LPTFS allele can confer reduced BVDV susceptibility in the heterozygous state despite expression of a functional wild-type CD46 allele. This result suggests the potential to more rapidly disseminate reduced BVDV susceptibility through conventional breeding using homozygous CD46-edited sires.

molecular biology↗

bioRxiv2026

Single-Cell Profiling of Dynamic Epicardial Cell States During Myocardial Infarction

Background: The epicardium is reactivated after myocardial infarction (MI); however, the gene expression profiles of post-MI adult epicardial subpopulations remain incompletely defined. Methods: Single-cell RNA sequencing was performed on lineage-traced Wt1+ epicardial cells from Wt1CreERT2/+; R26tdT/+; PdgfranGFP/+ adult mice after sham surgery or at 7 and 14 days after permanent artery ligation to induce MI. Immunostaining was performed on Wt1-lineage-traced cardiac tissue to validate spatial expression after ischemic injury. Results: Unbiased clustering identified nine transcriptionally distinct epicardial populations, encompassing mesothelial, fibroblast/mesenchymal, transitional, and proliferative phenotypes. Fibroblast-like epicardial cells (Wt1+/Pdgfra+) showed time-dependent expression profiles associated with upregulation of epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) gene programs. At 7 days post-MI, there was notable enrichment of genes related to chemokines and Wnt components. By 14 days post-MI, the expression profile shifted toward immune regulation. In contrast, a Wt1high/Msln+ population showed minimal upregulation of EMT gene programs but enhanced paracrine signaling related to wound healing and semaphorins, suggesting reactivation of reparative and angiogenic functions akin to those of the epicardium during embryonic development. Immunostaining and in situ hybridization fluorescence analyses validated laminar epicardial cell placement after MI, comprising a surface Msln+ sheet, an overlapping Wt1-lineage band, and a subadjacent PDGFR+ and Periostin+ compartment that expands 7-14 days after MI and regresses by day 28 post-ischemia. Conclusions: Our data define epicardial gene programs in which a signaling epithelial cell surface overlays an effector mesenchymal cell stroma to coordinate angiogenesis, leukocyte recruitment, and ECM remodeling. This study presents the first integrated single-cell atlas of epicardial-derived cells across multiple post-ischemic timepoints, offering new insights into their reparative potential and dynamic signaling diversity in the injured adult heart.

molecular biology↗

bioRxiv2026

Stop codon readthrough in Trichomonas is a mechanism for gene expression regulation and expanding protein function

Trichomonas vaginalis is the causative agent of trichomoniasis, a common sexually transmitted infection among women of reproductive and peri-menopausal age. The parasite has an unusually large genome, rich in complex repeats, including a vast repertoire of transposable elements and multi-copy gene families. Since very few T. vaginalis genes have introns, gene expression is usually straightforward, with ribosomal translational machinery proceeding from a start codon to the next in-frame stop codon of an unspliced poly(A)denylated mRNA. However, our previous studies raised the possibility of T. vaginalis gene expression involving stop codon readthrough (SCR), where transcription through in-frame stop codons produces longer-than-predicted mRNAs that translate to fully functional proteins. Here, we leverage long-read RNA-seq and new chromosome-scale assemblies of two T. vaginalis strains and two avian sister species to investigate and characterize ~1,400 long, mature mRNAs that contain more than one predicted protein-coding gene transcribed from what we call '' RT genes '', composites of adjacent predicted genes. We first identify RT genes in a second T. vaginalis strain and in close relatives T. vaginalis-like and T. stableri, indicating that this phenomenon is conserved among Trichomonas species and strains. Second, we find transcripts of RT genes to be more abundant by many orders of magnitude than monocistronic genes. Third, we found the distance between predicted genes within RT genes to be significantly shorter than between adjacent independent predicted genes. Fourth, functional annotation revealed that RT genes encode at least 50 distinct protein functions, suggesting that this unusual transcriptional mechanism has a role in an array of biological processes in Trichomonas. Our results from two Trichomonas species suggest that SCR is an important mechanism controlling gene expression and the diversity of protein function in this parasite.

molecular biology↗

bioRxiv2026

Male Age and Sexual Maturity: Lipopolysaccharide-induced tumor necrosis factor influences sperm quality and reproduction in Anopheles culicifacies

Elucidating the biological and molecular mechanisms that govern male fertility and mating behavior in mosquitoes is critical for optimizing genetic and sterile insect technique-based vector control strategies. Here, we examined age-related changes in male reproductive capacity in Anopheles culicifacies, using female egg output as an indirect indicator of male fertility. Our results demonstrated that male reproductive age follows a non-linear pattern of fertility. Morphometric analysis from emergence to day 13 post-eclosion revealed a strong correlation between seminal vesicle capacity and female fecundity, suggesting that age-dependent gonadal development directly influences reproductive potential. At the molecular level, we identified AcLITAF6 as a key regulator of male reproductive homeostasis. RNAi-mediated knockdown of AcLITAF6 impaired apoptosis-associated and phagocytic clearance, reduced sperm viability, and decreased female productive outcomes. Conclusively, we reveal a previously unrecognized role of LITAF in sperm quality control and male reproductive fitness, highlighting AcLITAF6 as a potential target for mosquito population suppression strategies.

developmental biology↗

bioRxiv2026

From Prompt to Provenance: BloClaw, a Capability-Gated AI4S Workstation for Auditable Computational Biology

Scientific agents can produce plausible answers while remaining unable to establish whether the computation behind an answer is executable, recoverable, or reproducible. We present BloClaw, an AI4S workstation built around a simple principle: a scientific agent should know what it can do, show how it did it, and state what remains unvalidated. Each capability declares an execution state, input constraints, dependencies, expected outputs, and scientific limitations. Natural-language requests are translated into structured tasks, validated against this registry, executed through scientific tools, and recorded in a provenance-aware Living Lab Notebook. The system is designed to detect invalid inputs, failed tool calls, missing dependencies, and remote timeouts, and to route them to repair, retry, or escalation. The implemented and tested scope comprises RDKit-based molecular property and rule screening, protein structure analysis, docking-pose inspection, 3D visualization, and structured reporting. We demonstrate the workflow on a PubChem-retrieved osimertinib structure and a supplied 6LU7 docking artifact: the former yields deterministic descriptors (molecular weight 499.619 Da, cLogP 4.5098, TPSA 87.55 A^2), while the latter contains 2,387 protein ATOM records, 309 residues, and nine pose records. These examples are workflow demonstrations, not efficacy or affinity studies. Beyond retrospective prediction, the manuscript specifies a prior-minimized constructive mode in which a desired function is compiled into explicit physical, chemical, and systems constraints, candidate mechanisms are simulated, and observations are reintroduced for calibration and falsification; this is a proposed extension rather than a result of the present case studies. We describe an evaluation protocol that compares BloClaw with a standard single-agent workflow and fixed-script execution using task completion, scientific correctness, recovery success, provenance completeness, reproducibility, human review time, latency, and cost. This manuscript reports the system design, verified capability boundary, deterministic software artifacts, and a reproducible evaluation protocol; it does not claim benchmark improvements before those experiments are run. BloClaw is an execution and accountability layer for AI-assisted research, complementing expert review and experimental validation rather than replacing them.

bioinformatics↗

bioRxiv2026

β4-integrins safeguard nuclear mechanics to suppress prostate cancer progression

Prostate cancer (PCa) progression is accompanied by profound alterations in cell-extracellular matrix (ECM) adhesion, nuclear architecture and mechanical adaptability, yet the molecular mechanisms linking these processes remain poorly understood. Hemidesmosomes (HDs), formed by 6{beta}4-integrins, anchor epithelial cells to the basement membrane and couple extracellular forces to the intermediate filament (IF) cytoskeleton. Here, we identify a previously unrecognized tumor-suppressive function of {beta}4-integrins in preserving nuclear integrity in prostate epithelial cells. Loss of {beta}4-integrins disrupted the cytokeratin-5 network and its coupling to the nucleus, leading to nuclear softening, lamin remodeling, reduced heterochromatin content and enhanced confined migration. Unexpectedly, proximity-labeling proteomics revealed that {beta}4-integrins engage nuclear pore complex (NPC) components in an 6-independent manner, particularly upon HD disassembly. Selected interactions were validated using proximity ligation and co-immunoprecipitation assays. {beta}4-integrin loss was associated with enlarged nuclear pores and aberrant nucleocytoplasmic transport, including nuclear accumulation of YAP1. Consistent with these findings, reduced {beta}4-integrin expression in a large PCa tissue cohort correlated with altered nuclear morphology, adverse clinicopathological features, metastatic progression, and poor patient survival. Collectively, our study establishes {beta}4-integrins as a critical molecular link between cell-ECM adhesion, nuclear mechanics and genome integrity.

cancer biology↗

bioRxiv2026

LINC00536 regulates transcriptional repressor TRPS1 in breast cancer

Metastatic breast cancer with complex molecular mechanisms of progression accounts for most cancer related deaths in women. To improve diagnosis and drug development, it is important to identify novel biomarkers and critical molecular pathways involved in tumor initiation and progression. Here, we profiled and analyzed the expression of long non-coding RNAs (lncRNAs) from three distinct stages of tumor initiation and progression (hyperplasia, adenoma, and carcinoma). We performed RNAseq on tumor and mammary epithelial cells derived from ROSAmT/mG tumor and non-tumor mice. We identified 1913 differentially expressed protein coding genes and 324 lncRNAs in breast cancer cells of all stages compared with normal mammary epithelial cells. Pearson correlation analysis correlated 93 differentially expressed lncRNAs with protein coding genes, providing a comprehensive lncRNA-protein coding genes co-expression network. Among them, we focused on Gm19303 which was paired with the differentially expressed protein coding gene, transcriptional repressor GATA binding 1 (Trps1), and identified its human counterpart as LINC00536. Both LINC00536 and TRPS1 are only overexpressed in breast cancer and correlate with poor prognosis of patient from the TCGA and GTEx databases. Single cell RNAseq data from the Atlas of Human breast cancers further confirmed that TRPS1 is upregulated in human breast cancer compared to normal human mammary tissue with highest expression in ER+ subgroup. In summary, our study explored the potential role of lncRNAs in breast cancer initiation and progression. *Implications statement: Our findings imply that human LINC00536/TRPS1 serves as a novel and early biomarker of cancer progression and a potential therapeutic target for breast cancer.

cancer biology↗