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Results for “molecular biology”

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bioRxiv2022

Telomerase-independent maintenance of telomere length in a vertebrate

Telomere shortening places a key limitation on cell proliferation1. In all vertebrates explored to date, this limitation is overcome by telomerase-dependent telomere extension. Failure to maintain telomere length results in premature ageing and functional impairments in highly replicative cell populations as telomeres erode2. Alternative lengthening of telomeres (ALT), a telomerase-independent mechanism, compensates for telomere loss in a subset of human cancer cell lines 2. Here, we demonstrate that the highly regenerative newt Pleurodeles waltl lacks telomerase activity, contains telomeres distinct from all known vertebrates in both sequence and structure, and deploys ALT for physiological telomere maintenance. This constitutes the first report of telomerase-independent resolution of the end-replication problem at the whole-organism level within Chordata. One-Sentence SummaryP. waltl telomere biology is distinct amongst vertebrates and uses ALT at the whole-organism level.

molecular biology↗

bioRxiv2023

Phosphorylated trimeric SOSS1 complex and RNA polymerase II trigger liquid-liquid phase separation at double-strand breaks

The most toxic forms of DNA damage are double-strand breaks (DSBs). We have previously shown that RNA polymerase II (RNAPII), phosphorylated at tyrosine 1 (Y1P) on the C- terminal domain, transcribes RNA at DSBs to promote efficient DNA repair. However, it is still unknown how transcription is regulated at DSBs. Here, we show that the trimeric SOSS1 complex (hSSB1, INTS3, and c9orf80) binds to Y1P RNAPII in response to DNA damage, hSSB1 binds to R-loops, and formation of the SOSS1 complex is required for the coexistence of replication protein A (RPA) and hSSB1 at DSBs. The damage-activated tyrosine kinase c- Abl phosphorylates hSSB1 to enable its binding to Y1P RNAPII and its recruitment to DSBs. Finally, we show both in vitro and in vivo that the SOSS1 complex and RNAPII form dynamic repair compartments at DSBs via liquid-liquid phase separation (LLPS). The loss of the trimeric SOSS1 leads to impaired DNA repair, highlighting its biological importance in the RNA-dependent DNA damage response. TeaserTrimeric SOSS1 complex and transcription contribute to phase separation at double-strand DNA breaks.

molecular biology↗

bioRxiv2024

G-quadruplexes in Haloferax volcanii

Archaea, a domain of microorganisms found in diverse environments including the human microbiome, represent the closest known prokaryotic relatives of eukaryotes. This phylogenetic proximity positions them as a relevant model for investigating the evolutionary origins of nucleic acid secondary structures such as G-quadruplexes (G4s), which play regulatory roles in transcription and replication. Although G4s have been extensively studied in eukaryotes, their presence and function in archaea remain poorly characterized. In this study, a genome-wide analysis of the halophilic archaeon Haloferax volcanii identified over 5, 800 potential G4-forming sequences. Biophysical validation confirmed that many of these sequences adopt stable G4 conformations in vitro. Using G4-specific detection tools and super-resolution microscopy, G4 structures were visualized in vivo in both DNA and RNA across multiple growth phases. Comparable findings were observed in the thermophilic archaeon Thermococcus barophilus. Functional analysis using helicase-deficient H. volcanii strains further identified candidate enzymes involved in G4 resolution. These results establish H. volcanii as a tractable archaeal model for G4 biology.

molecular biology↗

bioRxiv2025

Hypothetical LOC Genes as Biomarkers of Spaceflight Adaptation: A Comparative Study from ISS, Suborbital, and Earth-Based Experiments

Microgravity constitutes one of the most profound environmental stressors encountered by humans during spaceflight, capable of altering fundamental cellular processes and gene regulatory networks. While the effects of spaceflight on well-characterized protein-coding genes have been widely documented, little is known about the behavior of uncharacterized or poorly annotated genomic regions under these conditions. LOC (Locus) genes, often classified as long non-coding RNAs and excluded from conventional analyses, represent a largely unexplored component of the human transcriptome. In this study, we systematically investigated the transcriptional responses of LOC genes as part of the MESSAGE (Microgravity Associated Genetics) Science Mission, Turkiyes first human space biology initiative. Peripheral blood samples were collected from astronauts across five mission phases: pre-launch baseline, post-suborbital flight ([~]100 km), and on International Space Station (ISS) Days 4, 7, and 10 ([~]400 km). RNA-Seq analyses revealed six LOC genes with statistically significant expression changes (p < 0.05, Kruskal-Wallis test), alongside additional transcripts that, while not statistically significant, exhibited biologically meaningful temporal fluctuations. These dynamic profiles included continuous upregulation, transient activation with subsequent return to baseline, and delayed induction at later ISS stages, highlighting the functional diversity of LOC responses. To assess their translational potential, Open Reading Frame (ORF) analyses were performed on significant transcripts, revealing conserved ORF structures--most notably identical ORF33 sequences in LOC124905103 and LOC124900480-- suggesting coding capacity. Phylogenetic analyses further supported evolutionary clustering consistent with expression and ORF similarities. Collectively, these findings challenge the notion of LOC genes as transcriptional noise, instead positioning them as candidate biomarkers and functional elements of microgravity adaptation. By extending space biology research into the "dark genome," this study provides novel insights with potential implications for astronaut health monitoring and therapeutic development in long-duration missions.

molecular biology↗

bioRxiv2019

Mammalian Y RNAs are modified at discrete guanosine residues with N-glycans

Glycans modify lipids and proteins to mediate inter- and intramolecular interactions across all domains of life. RNA, another multifaceted biopolymer, is not thought to be a major target of glycosylation. Here, we challenge this view with evidence that mammalian cells use RNA as a third scaffold for glycosylation in the secretory pathway. Using a battery of chemical and biochemical approaches, we find that a select group of small noncoding RNAs including Y RNAs are modified with complex, sialylated N-glycans (glycoRNAs). These glycoRNA are present in multiple cell types and mammalian species, both in cultured cells and in vivo. Finally, we find that RNA glycosylation depends on the canonical N-glycan biosynthetic machinery within the ER/Golgi luminal spaces. Collectively, these findings suggest the existence of a ubiquitous interface of RNA biology and glycobiology suggesting an expanded role for glycosylation beyond canonical lipid and protein scaffolds.

molecular biology↗

bioRxiv2026

A Transformer-based Multi-omics Model for Translation Efficiency in S. cerevisiae

Precise regulation of protein synthesis is fundamental to cellular homeostasis and remains a primary target for synthetic biology applications. However, the non-linear relationship between mRNA abundance and protein levels presents complexities that poses challenges for predictive engineering. Here, we present TRIM, a Transformer-based RNA Inference Model that leverages full-length mRNA sequences and multi-omics data to predict translation efficiency. By employing a Parallel Expert Mixer, TRIM achieves robust prediction accuracy (R2 [≥] 0.8,Pearson r [≥] 0.9). Trained on multimodal data from massive Saccharomyces cerevisiae isolates, TRIM demonstrates outstanding biological interpretability, helping to decipher complex translational patterns such as synergistic effects between bases, sequence-dependent codon preference in different stages, and distinct attention on key secondary structures. These results indicate that the integration of multi-omics data with holistic sequence modeling can effectively decode the cis-regulatory grammar of translation as well as providing a scalable and interpretable generative framework for future synthetic biology engineering. Availability and ImplementationThe source code and data used to produce the results and analyses presented in the manuscript are available from Github (https://github.com/ZeusLiu666/TRIM).

Molecular Biology↗

bioRxiv2021

Investigating densities of Symbiodiniaceae in two species of Antipatharians (black corals) from Madagascar

Here, we report the first methodological approach to investigate the presence and estimate the density of Symbiodiniaceae cells in corals of the order Antipatharia subclass Hexacorallia, known as black corals. Antipatharians are understudied ecosystem engineers of shallow (<30 m depth), mesophotic (30-150 m) and deep-sea (>200 m) reefs. They provide habitat to a vast number of marine fauna, enhancing and supporting coral reefs biodiversity globally. Nonetheless, little biological and ecological information exists on antipatharians, including the extent at which global change disturbances are threatening these corals. The assumption that they were exempted from threats related to climate change was challenged by findings of high density of dinoflagellates within three antipatharian colonies. Further methodical studies were necessary to investigate the regularity of these findings. An integrated design combining microscopy and molecular techniques was used to investigate the presence and estimate density of Symbiodiniaceae cells within two antipatharians species -Cupressopathes abies and Stichopathes maldivensis -from shallow and mesophotic reefs of SW Madagascar. Symbiodiniaceae-like cells were found within the two species from both shallow and mesophotic reefs, although the overall cell density was very low (0-4 cell mm-3). These findings suggest that high abundance of Symbiodiniaceae is not characteristic of antipatharians, which has relevant implications considering disruptions associated to climate change affecting other corals. However, the high densities of dinoflagellates found in antipatharian colonies exposed to higher light irradiance in other studies should be further examined.

molecular biology↗

bioRxiv2025

Small activating RNA AW1-51 (CEBPA-51) elicits targeted DNA demethylation to promote gene activation

Small activating RNAs are short double-stranded RNAs designed to upregulate transcription of target genes. By this virtue, they can be used to restore expression of genes frequently silenced in cancer. AW1-51 (also referred to as CEBPA-51), the first small activating RNA therapeutic to enter clinical evaluation, has demonstrated biological activity and safety in Phase II trials for hepatocellular carcinoma, both as monotherapy and in combination with sorafenib, and in Phase 1a/1b in combination with pembrolizumab for patients with advanced solid tumors. It targets the master regulator CCAAT enhancer-binding protein alpha, abnormally silenced by DNA methylation in a wide range of hematological and non-hematological malignancies. However, the molecular events enabling this mechanism are only partially elucidated. In this study, we uncovered the molecular basis for AW1-51-induced transcriptional reactivation of CCAAT enhancer-binding protein alpha demonstrating that by directly promoting DNA demethylation of its promoter restores its expression, protein synthesis, and consequently cell differentiation. These findings unveil AW1-51 as a prototype for RNA-based precision medicine enabling conditional expression of CCAAT enhancer-binding protein alpha in diseases characterized by aberrant gene silencing and extending its potential therapeutic impact beyond cancer.

molecular biology↗

bioRxiv2016

Gene regulation mechanism in drought-responsive grapevine leaves as revealed by transcriptomic analysis

Grapevine is economically important and widely cultivated fruit crop, which is seriously hampered by drought worldwide. It is necessary to understand the impact of glitches incurred by the drought on grapevine genetic resources. Therefore, in the present study RNA-sequencing analysis was performed using cDNA libraries constructed from both drought-stress and control plants. Results yielded, a total of 12,451 differentially expressed genes (DEGs) out of which 8,022 genes were up-regulated and 4,430 were down-regulated. Further physiological and biochemical analyses were carried out to validate the various biological processes involved in the development of grapevine in response to drought stress. Results also showed that decrease in rate of stomatal conductance in-turn decrease the photosynthetic activity and CO2 assimilation rate in the grapevine leaves and most ROS detoxification systems, including stress enzymes, stress related proteins and secondary metabolites were strongly induced. Moreover, various hormones were known to be induced in the present study in response to drought. Overall the present study concludes that these DEGs play both positive and negative role in drought tolerance by regulating different biological pathways of grapevine. However our findings have provided valuable gene information for future studies of abiotic stress in grapevine and other fruit crops.

Molecular Biology↗

bioRxiv2024

PCA-Plus: Enhanced principal component analysis with illustrative applications to batch effects and their quantitation

BackgroundPrincipal component analysis (PCA), a standard approach to analysis and visualization of large datasets, is commonly used in biomedical research for detecting similarities and differences among groups of samples. We initially used conventional PCA as a tool for critical quality control of batch and trend effects in multi-omic profiling data produced by The Cancer Genome Atlas (TCGA) project of the NCI. We found, however, that conventional PCA visualizations were often hard to interpret when inter-batch differences were moderate in comparison with intra-batch differences; it was also difficult to quantify batch effects objectively. We, therefore, sought enhancements to make the method more informative in those and analogous settings. ResultsWe have developed algorithms and a toolbox of enhancements to conventional PCA that improve the detection, diagnosis, and quantitation of differences between or among groups, e.g., groups of molecularly profiled biological samples. The enhancements include (i) computed group centroids; (ii) sample-dispersion rays; (iii) differential coloring of centroids, rays, and sample data points; (iii) trend trajectories; and (iv) a novel separation index (DSC) for quantitation of differences among groups. ConclusionsPCA-Plus has been our most useful single tool for analyzing, visualizing, and quantitating batch effects, trend effects, and class differences in molecular profiling data of many types: mRNA expression, microRNA expression, DNA methylation, and DNA copy number. An early version of PCA-Plus has been used as the central graphical visualization in our MBatch package for near-real-time surveillance of data for analysis working groups in more than 70 TCGA, PanCancer Atlas, PanCancer Analysis of Whole Genomes, and Genome Data Analysis Network projects of the NCI. The algorithms and software are generic, hence applicable more generally to other types of multivariate data as well. PCA-Plus is freely available in a down-loadable R package at our MBatch website.

bioinformatics↗

bioRxiv2024

Spatial mapping of dextran sodium sulphate-induced intestinal inflammation and its systemic effects

Inflammatory bowel disease (IBD) is a multifactorial disease and patients frequently experience extraintestinal manifestations affecting multiple sites. Causes of systemic inflammation remain poorly understood but molecules originating from the intestine likely play a role, with microbial and host small molecules polarizing host immune cells towards a pro- or anti-inflammatory phenotype. Using the dextran sodium sulphate (DSS) mouse model, which mimics the disrupted barrier function, microbial dysbiosis and immune cell dysregulation of IBD, we investigated metabolomic and phenotypic changes at intestinal and systemic sites. Using spatial biology approaches we mapped distribution and relative abundance of molecules and cell types across a range of tissues revealing significant changes in DSS-treated mice. Molecules identified as contributing to the statistical separation of treated from control mice were spatially localized within organs to determine their effects on cellular phenotypes through imaging mass cytometry. This spatial approach identified both intestinal and systemic molecular drivers of inflammation, including several not previously implicated in inflammation linked to IBD or the systemic effects of intestinal inflammation. Metabolic and inflammatory pathway interplay underpins systemic disease and determining drivers at the molecular level may aid the development of new targeted therapies.

molecular biology↗

bioRxiv2025

The autophagy receptor Ncoa4 controls PPARγ activity and thermogenesis in brown adipose tissue

Adipose tissue dysfunction leads to a variety of deleterious systemic consequences including ectopic lipid deposition and impaired insulin sensitivity. PPAR{gamma} is a major regulator of adipocyte differentiation and functionality and is thus a determinant of systemic metabolic health. We recently reported that deletion of adipocyte fatty acid synthase (AdFasnKO) impairs autophagy in association with a striking upregulation of genes controlled by PPAR{gamma}, including thermogenic uncoupling protein 1 (Ucp1). In this present study, screening for PPAR{gamma} coactivators regulated by autophagy revealed a protein denoted as Nuclear receptor coactivator 4 (Ncoa4), known to mediate ferritinophagy and interact with PPAR{gamma} and other nuclear receptors. Indeed, we found Ncoa4 is upregulated in the early phase of adipocyte differentiation and is required for adipogenesis. Ncoa4 is also elevated in FasnKO adipocytes and necessary for full upregulation of Ucp1 expression in vitro, even in response to norepinephrine. Consistent with these findings, adipose-selective knockout of Ncoa4 (AdNcoa4KO mice) impairs Ucp1 expression in brown adipose tissue and cold-induced thermogenesis. Adipose-selective double KO of Fasn plus Ncoa4 (AdFasnNcoa4DKO mice) prevents the upregulation of classic PPAR{gamma} target genes normally observed in the white adipose tissue of AdFasnKO mice, but not thermogenic Ucp1 expression. These findings reveal Ncoa4 is a novel determinant of adipocyte PPAR{gamma} activity and regulator of white and brown adipocyte biology and suggest that manipulation of autophagy flux modulates PPAR{gamma} activity and key adipocyte functions via Ncoa4 actions.

molecular biology↗

bioRxiv2025

Application of post glycosylation modifying enzymes for mass spectrometry imaging of modified N-glycans in situ.

Glycans are essential components of cells and are involved in innumerable biological processes. Their structural diversity and complexity present unique analytical challenges. Glycans are comprised of various types of monosaccharides that are linked together at different positions and with varied stereochemistry. In addition, glycans are frequently decorated with a diverse set of chemical modifications, termed post-glycosylation modifications (PGMs). Characterization of PGMs is essential for a thorough understanding of glycans, however, the technical challenges and low throughput of current methodologies have limited our understanding of these modifications. Here we demonstrate a novel approach for rapid visualization of specific PGMs present in tissue N-glycans by applying PGM-targeting enzymes to mass spectrometry imaging (MSI). The method enables in situ investigation of glycans with PGMs en masse, identifying the sugar residue and position modified, as well as visualizing the spatial distribution of each modified N-glycan in tissues. As the repertoire of PGM-targeting enzymes expands, we anticipate this approach will enable a better understanding of PGM distribution within a dynamic N-glycome. This may yield both new biological insights and the potential for identification of novel disease biomarkers.

molecular biology↗

bioRxiv2018

Tdrd6a regulates the aggregation of Buc into functional subcellular compartments that drive germ cell specification

In recent years, it has become clear that phase separation represents an important class of subcellular compartmentalization. However, relatively little is known about how the formation or disassembly of such compartments is regulated. In zebrafish, the Balbiani body (Bb) and the germ plasm (Gp) are phase-separated structures essential for germ cell specification and home to many germ cell-specific mRNAs and proteins. Throughout development, these structures range from a single large aggregate (Bb), to a dispersed state and back to relatively large assemblies (Gp). Formation of the Bb requires Bucky ball (Buc), a protein with prion-like properties. We found that the multi-tudor domain-containing protein Tdrd6a interacts directly with Buc, affecting its mobility and aggregation properties. Importantly, lack of this regulatory interaction leads to significant defects in germ cell development. Our work presents a new mechanism for how prion-like protein-aggregations can be regulated and highlights the biological relevance of such regulatory events.

molecular biology↗

bioRxiv2026

HDAC5-encoded Microprotein NISM Mediates Nucleolar Formation and Ribosomal RNA Synthesis

Ribosome biogenesis is the process by which ribosomal RNA (rRNA) and ribosomal proteins are synthesized, processed, and assembled into functional ribosomes. This process begins in the nucleolus, a multiphase liquid condensate. Here, we discover an arginine-rich disordered nucleolar microprotein encoded within the HDAC5 5'-UTR that we termed Nucleolar Integrity and Stress Microprotein (NISM). NISM overexpression leads to impaired rDNA transcription, triggering nucleolar stress, p53 activation, and suppressed proliferation. NISM knockout causes disruption of nucleolar structure and also induces p53 activation. Mechanistically, NISM interacts with the DExH-box RNA helicase DHX9 and regulates its activities related to pre-rRNA synthesis. Computational analyses and polymer physics-based mathematical modeling revealed that NISM coordinates nucleolar formation and pre-rRNA synthesis by enhancing the liquid-liquid phase separation of DHX9. This study establishes NISM as a regulator of nucleolar biology and deepens our understanding of how disordered microproteins can facilitate the formation of membraneless organelles.

molecular biology↗

bioRxiv2026

Expanding the chemical diversity of RNA by transcriptional incorporation of amino acid- and glycosyl-modified nucleotides

With the increasing interest in RNA-based therapies, there is a pressing need to incorporate new chemistries into more complex RNA molecules. These modifications can protect RNA from degradation, improve its pharmacokinetics, and enhance its targeting properties. Here we describe the enzymatic synthesis of chemically modified RNA derivatives using a mutant T7 RNA polymerase to incorporate 23 different base modifications alongside stabilizing ribose modifications, such as 2'-fluoro and 2'-deoxy groups. To investigate the impact on transcription efficiency and fidelity, we employed a pool of 38 template sequences and analyzed the transcripts by next-generation sequencing of the cDNA. Results demonstrated that all modifications were successfully incorporated into RNA, with transcription efficiency influenced by three main factors: type of modification, base modified, and the sequence context. Misincorporation levels during transcription and reverse transcription into cDNA were generally low (<1%) but included noticeable exceptions for some nucleobase-modification combinations. As a robust proof-of-concept we demonstrated the selection of Histidine-U modified aptamer, relying on multiple rounds of transcription and amplification, binding Influenza hemagglutinin protein with low nanomolar KD. We anticipate that this work will significantly contribute to the design and production of chemically modified RNAs with novel functionalities, advancing applications in biomedicine and synthetic biology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/720138v2_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@29b6daorg.highwire.dtl.DTLVardef@a3c425org.highwire.dtl.DTLVardef@1a27a4aorg.highwire.dtl.DTLVardef@ab0e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2017

Multiple Poliovirus-Induced Organelles Suggested By Comparison Of Spatiotemporal Dynamics Of Membranous Structures And Phosphoinositides

Poliovirus (PV) infection induces membranes with elevated levels of phosphatidylinositol-4-phosphate (PI4P) and invaginated, tubular structures that appear as vesicular clusters in cross section. Here, we characterize PV mutants, termed EG and GG, which exhibit aberrant proteolytic processing of the P3 precursor that can delay the onset of genome replication and/or impair virus assembly. For WT PV, changes to the PI4P pool were observed as early as 30 min post-infection. PI4P remodeling occurred even in the presence of guanidine hydrochloride, a replication inhibitor. Vesicular clusters were not apparent until 3 h post-infection, a time too slow for these structures to be responsible for genome replication. Delays in the onset of genome replication observed for EG and GG PVs were explained completely by the reduced kinetics of virus-induced remodeling of PI4P pools, consistent with PI4P serving as a marker of the genome-replication organelle. Infectious virus produced by GG PV is known to be reduced nearly 5 logs. We show that GG PV was unable to make virus-induced vesicular clusters. Instead, GG PV-infected cells accumulated elongated tubules. Our results are consistent with the existence of distinct organelles for genome-replication and virus assembly. We suggest that the pace of formation and spatiotemporal dynamics of PV induced organelles may be set by the rate of P3 precursor processing to form 3AB and/or 3CD proteins.\n\nAUTHOR SUMMARYAll positive-strand RNA viruses replicate their genomes in association with host cell membranes. PV does not just remodel existing membranes, but induces membranes with unique structure and lipid composition. There has been some suggestion that the functions of the PV induced structures observed during infection may not be those that perform genome-replication. This study uses kinetic analysis of virus-induced membrane formation and PI4P induction by two PV mutants to provide evidence for the existence of a virus-induced genome-replication organelle distinct from a second organelle, the absence of which impairs virus assembly. In addition, our studies suggest that formation of both organelles may require participation of viral proteins, 3AB and/or 3CD. Therefore, this study provides a new perspective on the cell biology of PV infection and should inspire a fresh look at picornavirus-induced organelles, their functions and the role of P3 proteins in their formation.

molecular biology↗

bioRxiv2020

CloneSeq: A Highly Sensitive Single-cell Analysis Platform for Comprehensive Characterization of Cells from 3D Culture

Single-cell assays have revealed the scope and importance of heterogeneity in many biological systems. However, in many cases, single cell limited sensitivity is a major hurdle for uncovering the full range of cellular variation. To overcome this limitation, we developed a complementary single cell technology, CloneSeq that combines clonal expansion under controlled culture conditions inside three-dimensional (3D) hydrogel spheres and droplet-based RNA sequencing (RNA-seq). We show that unlike single cell transcriptomes, clonal cells maintain cell states and share similar transcriptional profiles. CloneSeq analysis of Non-small-cell lung carcinoma (NSCLC) cells revealed the presence of novel cancer-specific subpopulations, including cancer stem-like cells (CSLCs). Standard single cell RNA-seq assays as well as cell-to-clone tracing by genetic barcoding failed to identify these rare CSLCs. In addition to CSLCs, clonal expansion within 3D soft microenvironments supported cellular stemness of embryonic stem cells (ESCs) that retained their pluripotent state in the absence of pluripotent media and improved epigenetic reprogramming efficiency of mouse embryonic fibroblasts. Our results demonstrate the capacity of CloneSeq, which can be effectively adapted to different biological systems, to discover rare and previously hidden subpopulations of cells, including CSLCs, by leveraging the broader expression space within clones.

molecular biology↗