Biology subjects

Cervera, A.

Publications and source records attributed to Cervera, A..

7 recordsLinked to original sources

bioRxiv2026

Metabolic cost sets the shear stress profile of optimal vascular trees

Vascular remodeling responds to local wall shear stress, but transport efficiency belongs to the network as a whole. We connect these scales by minimizing dissipation under a fixed maintenance budget, with vessel cost proportional to mass raised to an exponent b. At an optimum, dissipated power is proportional to vessel cost. This yields the shear set point |{tau} | {propto} r^(b-1){ell}^(b-1)/2 for radius r and length {ell}, with uniform shear recovered at b = 1. The associated local adaptation rule decreases the global functional, although the topology it reaches retains a memory of development. Simulations with 400 and 700 sinks show that staged growth improves transport mainly by allowing pruned connections to regrow. Fluctuating demand sustains loops without increasing the maintenance budget. The local condition fixes allocation on a given support, whereas growth and variable demand shape the topology that survives.

biophysics↗

bioRxiv2024

Self-cleaving ribozymes conserved in RNA viruses unveil a new role in protein translation

Small self-cleaving ribozymes are catalytic RNAs originally discovered in viroid-like agents, which are replicating circular RNAs (circRNAs) postulated as relics of a prebiotic RNA world. In the last decade, however, small ribozymes have also been detected across the tree of life, from bacterial to human genomes, and more recently, in unusual circRNA viruses. Here we report the conserved occurrence of diverse small ribozymes within the linear genomes of typical double- and single-stranded RNA virus families from fungi and plants. Type I hammerhead ribozyme motifs occur in the 5-UTR regions of chrysovirids and fusarivirids, displaying self-cleaving activity in vitro and in vivo. Similar hammerhead, as well as hepatitis delta and twister ribozymes, are also found in diverse megabirna-, hypo-, fusagra-, toti-or tombus-like viruses among others. The ribozymes occur not only as isolated motifs within UTRs but also as tandem pairs that encompass small RNA segments (186-399 nt) resembling Zetavirus-like sequences. In vivo characterization of the 5-UTR with a ribozyme from a chrysovirid revealed that the RNA-cleaving activity is essential for protein translation initiation in fungi. Analogous experiments in plants with diverse ribozyme motifs indicated that just the presence of a self-cleaving activity can induce cap-independent translation. We conclude that RNA self-cleaving activity, historically linked to the rolling circle replication of viroid-like circRNAs, appears to be co-opted by linear RNA viruses for translational roles.

microbiology↗

bioRxiv2024

Retrotransposon expression is upregulated by aging and suppressed during regeneration of the limb in the axolotl (Ambystoma mexicanum)

The axolotl (Ambystoma mexicanum) has a great capacity to regenerate its tissues and whole-body parts; however, the fidelity and success of its regenerative process diminish with age. Retrotransposons make up the largest portion of the axolotl genome, and their expression may be involved in this age-related decline. Through an integrative analysis of repetitive element expression using RNA-seq, we show that Ty3 retrotransposons are highly upregulated in the axolotl as an effect of chronological aging. Other non-LTR transposons, including LINE-1, function as hubs of gene coexpression networks involved in muscle development, N-methyltransferase activity, amyloid proteolysis, and regulation of apoptosis and connective tissue replacement, which are also suppressed by the increase in age. In contrast, we find that during regeneration of the limb these pathways and the expression of Ty3 retrotransposons are distinctly downregulated. Although the blastema is able to readjust most of the transposon dysregulation caused by aging, there are still several elements that remain affected and may have an impact in the metabolic and immune responses during the regenerative process. We also report that numerous C2H2-ZFPs, especially KRAB-ZPFs, are coexpressed with hub retrotransposons, which reveals their potential as important regulators of transposable element expression during aging and regeneration. This integrative analysis provides a comprehensive profile of retrotransposon expression through chronological aging and during limb regeneration in the axolotl and indicates that transposable elements are responsive to physiological changes in a tissue-specific way and participate in the gene co-regulatory networks underlying the regenerative process. Graphical abstract.Transcriptomic analyses of adult and sub-adult axolotls offer an insight into the potential role of retrotransposons during limb regeneration and how they are affected by chronological aging. Retrotransposons of the Ty3 superfamily are usually suppressed during regeneration, but after experiencing a significant upregulation through the aging of the axolotl, their regulation during tissue repair is limited. It has been reported that the success of the axolotls regenerative process diminishes with age. Our findings show that Ty3 and other transposon families, such as LINE-1, are involved in the gene regulatory networks that suppress muscle development, apoptosis control, and tissue replacement due to aging. These results suggest that repetitive element expression may indirectly constrain the regenerative capacities of older axolotls. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/588033v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1d10844org.highwire.dtl.DTLVardef@75d566org.highwire.dtl.DTLVardef@d4af6org.highwire.dtl.DTLVardef@b47b47_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2022

Extant hybrids of RNA viruses and viroid-like elements

Earths life may have originated as self-replicating RNA. Some of the simplest current RNA replicators are RNA viruses, defined by linear RNA genomes encoding an RNA-dependent RNA polymerase (RdRP), and subviral agents with single-stranded, circular RNA genomes, such as viroids encoding paired self-cleaving ribozymes. Amongst a massive expansion of candidate viroid and viroid-like elements, we report that fungal pathogens, ambiviruses, are viroid-like elements which undergo rolling circle replication and encode their own viral RdRP, thus they are a distinct hybrid infectious agent. These findings point to a deep evolutionary history between modern RNA viruses and sub-viral elements and offer new perspectives on the evolution of primordial infectious agents, and RNA life. One-Sentence SummaryNovel infectious agents resembling self-cleaving viroid-like RNAs whilst encoding a viral RNA-dependent RNA polymerase.

microbiology↗

bioRxiv2019

Small circRNAs with self-cleaving ribozymes are frequently expressed in metazoan transcriptomes

Ribozymes are catalytic RNAs present in modern genomes but considered as remnants of a prebiotic RNA world. The paradigmatic hammerhead ribozyme (HHR) is a small self-cleaving motif widespread from bacterial to human genomes. Here, we report that most of the classical type I HHRs frequently found in the genomes of diverse animals are contained within a novel family of non-autonomous non-LTR retrotransposons. These retroelements are expressed as abundant linear and circular RNAs of [~]170-400 nt in different animal tissues. In vitro analyses confirm an efficient self-cleavage of the HHRs harboured in invertebrate retrozymes, whereas those in retrozymes of vertebrates, such as the axolotl, require to act as dimeric motifs to reach higher self-cleavage rates. Ligation assays of retrozyme RNAs with a protein ligase versus HHR self-ligation indicate that, most likely, tRNA ligases and not the ribozymes are involved in the step of RNA circularization. Altogether, these results confirm the existence of a new and conserved pathway in animals and, likely, in eukaryotes in general, for the efficient biosynthesis of RNA circles through small ribozymes, which will allow the development of biotechnological tools in the emerging field of circRNAs.

genomics↗

bioRxiv2019

Direct conversion of human fibroblasts to liver cancer cells

Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation, and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.

cancer biology↗

bioRxiv2017

Modified penetrance of coding variants by cis-regulatory variation shapes human traits

Coding variants represent many of the strongest associations between genotype and phenotype, however they exhibit inter-individual differences in effect, known as variable penetrance. In this work, we study how cis-regulatory variation modifies the penetrance of coding variants in their target gene. Using functional genomic and genetic data from GTEx, we observed that in the general population, purifying selection has depleted haplotype combinations that lead to higher penetrance of pathogenic coding variants. Conversely, in cancer and autism patients, we observed an enrichment of haplotype combinations that lead to higher penetrance of pathogenic coding variants in disease implicated genes, which provides direct evidence that regulatory haplotype configuration of causal coding variants affects disease risk. Finally, we experimentally demonstrated that a regulatory variant can modify the penetrance of a coding variant by introducing a Mendelian SNP using CRISPR/Cas9 on distinct expression haplotypes and using the transcriptome as a phenotypic readout. Our results demonstrate that joint effects of regulatory and coding variants are an important part of the genetic architecture of human traits, and contribute to modified penetrance of disease-causing variants.

genetics↗