Biology subjects

Andres-Leon, E.

Publications and source records attributed to Andres-Leon, E..

12 recordsLinked to original sources

bioRxiv2026

Circular RNA-associated QTLs show stronger association with splicing-QTLs than with expression-QTLs

IntroductionCircular RNA quantitative trait locus (circQTLs) have emerged as a class of regulatory variants, but their mechanistic basis remains poorly characterized. Understanding how genetic variation influences circRNA biogenesis is essential to clarify their role in post-transcriptional gene regulation. MethodsWe systematically compared circQTLs with matched splicing (sQTL) and expression (eQTL) datasets. Using bootstrap-based Jaccard similarity analyses, we quantified genomic overlap patterns and assessed their statistical significance. We further validated these findings across independent circQTL studies. In addition, we analyzed the genomic distribution of circQTLs to identify enrichment patterns across functional genomic regions. ResultscircQTLs exhibited a statistically significant but modestly stronger genomic overlap with sQTLs compared to eQTLs. This pattern was consistent across independent datasets despite limited reproducibility of individual circQTL signals. Genomic annotation revealed distinct distributional patterns, including depletion in exonic regions and relative enrichment in non-coding genomic contexts compared to other QTL classes. DiscussionTogether, these results suggest that circRNA-associated regulatory variation is preferentially linked to splicing-related mechanisms rather than transcriptional control of host genes. However, the modest effect size indicates that this relationship is not exclusive, and likely reflects a mixture of shared splice-site regulatory effects and additional mechanisms specific to back-splicing that are not captured by conventional sQTL or eQTL frameworks. This dual architecture positions circRNA biogenesis at the interface between splicing dynamics, RNA structure, and higher-order genomic organization, supporting circQTLs as a distinct layer of post-transcriptional gene regulation.

genetics↗

bioRxiv2026

Sex-biased Fibroblast Subpopulations and Transcriptional Programs Reveal Mechanisms of Skin Lesion Development in Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with pronounced sex differences: females are more frequently affected and males develop more severe skin fibrosis. The cellular mechanisms of this disparity remain unclear. Here we use single-cell transcriptomics of lesional, non-lesional, and healthy skin to define fibroblast states and sex-biased transcriptional programs during lesion development. We identify a sex-dependent divergence in SSc fibrotic regulation. Female fibroblasts exhibit heightened inflammatory signaling and canonical TGF-{beta}-driven extracellular matrix production, whereas male fibroblasts preferentially engage non-canonical TGF-{beta} pathways, mechanotransduction, and MYC-associated stress programs. We further reveal that the fibrotic lesional environment shows sex differences: SFRP2DPP4 fibroblasts predominate in females and COL11A1/COCH in males. Our findings uncover cellular mechanisms underlying sex differences in SSc fibrosis, highlight opportunities for sex-informed therapeutic strategies and underscore the necessity of integrating biological sex into precision medicine frameworks to identify divergent molecular drivers of fibrotic disease.

genomics↗

bioRxiv2026

Selective cross-TAD gene regulation by the Tcra enhancer during T cell development

Long-range functional enhancer-promoter (E-P) interactions typically occur within topologically associating domains (TADs), which facilitate contacts while restricting inter-domain communication. Although approximately one-third of E-P interactions cross TAD boundaries, they are considered non-functional and are only rarely reported during embryonic development. Here, we investigated the activity of the strong Tcra enhancer (E) positioned at the boundary between a centromeric TAD containing the T-lineage-specific Tcra-Tcrd locus and a telomeric TAD encompassing broadly expressed Dad1-to-Cdh24 genes. To directly assess E activity across TADs, we generated mice lacking E while preserving its associated CTCF-binding elements. As expected, E was required for T-cell specific Tcra-Tcrd transcription and normal T-cell development. In contrast, E did not activate Dad1 or Haus4 transcription in the telomeric TAD, indicating effective insulation by boundary elements. Unexpectedly, E selectively activated developmentally regulated Cdh24 expression, the most distal gene in the telomeric TAD, in thymocytes. These findings reveal a naturally occurring, functional cross-TAD E-P interaction during adult T-cell development, demonstrating that enhancers positioned at TAD boundaries can bypass topological insulation to selectively regulate distal gene expression.

genomics↗

bioRxiv2026

A dual-function variant on chromosome 17 regulates circRNA expression and splicing in multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system with a complex etiology. Recent genomic studies highlight the contribution of expression quantitative trait loci (eQTLs) in modulating gene expression and disease susceptibility. Given the emerging role of circular RNAs (circRNAs) in MS, we hypothesized that genetic variants may regulate circRNA expression through circRNA-specific eQTLs (circ-eQTLs). We performed a cis-circ-eQTL analysis integrating circRNA expression and whole-genome genotyping data from 30 MS patients and 18 healthy controls using a linear regression model adjusted for disease status and sex. Candidate circ-eQTLs were prioritized based on MS-associated regions and known splicing QTLs (sQTLs) from GTEx and validated in an independent cohort (67 MS, 64 controls). Association analysis in a larger cohort (2831 MS, 3191 controls) evaluated two candidate variants for MS risk. We identified 42,077 significant cis-circ-eQTLs and validated three. Two SNPs, rs7214410 and rs11079784, modulated hsa_circ_0106983 expression, and rs7214410 also acted as an sQTL affecting EFCAB13 splicing. rs7214410 showed stronger association with MS than rs11079784. Our findings reveal extensive genetic regulation of circRNA expression and highlight rs7214410 as a dual-function variant refining the MS susceptibility locus on chromosome 17.

genetics↗

bioRxiv2023

Multi-omics framework to reveal the molecular determinants of fermentation performance in wine yeast populations

BackgroundConnecting the composition and function of industrial microbiomes is a major aspiration in microbial biotechnology. Here, we address this question in wine fermentation, a model system where the diversity and functioning of fermenting yeast species is determinant of the flavor and quality of the resulting wines. ResultsFirst, we surveyed yeast communities associated with grape musts collected across wine appellations, revealing the importance of environmental (i.e., biogeography) and anthropic factors (i.e., farming system) in shaping community composition and structure. Then, we assayed the fermenting yeast communities in synthetic grape must under common winemaking conditions. The dominating yeast species defines the fermentation performance and metabolite profile of the resulting wines, and it is determined by the initial fungal community composition rather than the imposed fermentation conditions. Yeast dominance also had a more pronounced impact on wine meta-transcriptome than fermentation conditions. We unveiled yeast-specific transcriptomic profiles, leveraging different molecular functioning strategies in wine fermentation environments. We further studied the orthologs responsible for metabolite production, revealing modules associated with the dominance of specific yeast species. This emphasizes the unique contributions of yeast species to wine flavor, here summarized in an array of orthologs that defines the individual contribution of yeast species to wine ecosystem functioning. ConclusionsOur study bridges the gap between yeast community composition and wine metabolite production, providing insights to harness diverse yeast functionalities with the final aim to producing tailored high-quality wines.

microbiology↗

bioRxiv2023

reanalyzerGSE: tackling the everlasting lack of reproducibility and reanalyses in transcriptomics

SummaryIn the current context of transcriptomics democratization, there is an unprecedented surge in the number of studies and datasets. However, advances are hampered by aspects such as the reproducibility crisis, and lack of standardization, in particular with scarce reanalyses of secondary data. reanalyzerGSE, is a user-friendly pipeline that aims to be an all-in-one automatic solution for locally available transcriptomic data and those found in public repositories, thereby encouraging data reuse. With its modular and expandable design, reanalyzerGSE combines cutting-edge software to effectively address simple and complex transcriptomic studies ensuring standardization, up to date reference genome, reproducibility, and flexibility for researchers. Availability and implementationThe reanalyzerGSE open-source code and test data are freely available at both https://github.com/BioinfoIPBLN/reanalyzerGSE and 10.5281/zenodo.XXXX under the GPL3 license. Supplementary data are available.

bioinformatics↗

bioRxiv2022

Cell survival enabled by leakage of a labile metabolic intermediate

Many metabolic pathways are of ancient origin and have evolved over long periods of time (Noda-Garcia et al., 2018). Yet, new pathways can also emerge in short time scales in response, for instance, to the presence of anthropogenic chemicals in the environment (Copley, 2009). Models of metabolic pathway emergence and evolution often emphasize the acquisition of new reactions through horizontal gene transfer and promiscuous enzyme functionalities (Pal et al., 2005; Schulenburg & Miller, 2014; Copley, 2015; Noda-Garcia et al., 2018; Peracchi, 2018). A fundamentally different mechanism of metabolic innovation is revealed by the evolutionary repair experiments reported here. A block in the proline biosynthetic pathway that compromises cell survival is efficiently rescued by many single mutations (12 at least) in the gene of glutamine synthetase. The mutations cause the leakage to the intracellular milieu of a sequestered phosphorylated intermediate common to the biosynthetic pathways of proline and glutamine, thus generating a new route to proline. Metabolic intermediates may undergo a variety of chemical and enzymatic transformations, but are typically protected as shielded reaction intermediates or through channeling in multi-enzyme complexes and metabolons (Srere, 1987; Huang et al., 2001; Grunwald, 2018; Pareek et al., 2021). Our results show that intermediate leakage can readily occur and contribute to organismal adaptation. Enhanced availability of reactive molecules may enable the generation of new biochemical pathways. We therefore anticipate applications of mutation-induced leakage in metabolic engineering.

molecular biology↗

bioRxiv2021

Single-Cell Atlas of Common Variable Immunodeficiency reveals germinal center-associated epigenetic dysregulation in B cell responses

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is characterized by impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and a wide range of phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. We used single-cell epigenomics and transcriptomics to create a cell census of naive-to-memory B cell differentiation in a pair of CVID-discordant MZ twins. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B cells that mirror defective cell-cell communication defects following activation. These findings were validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naive-to-memory B-cell transition in CVID and reveal links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, paves the way for future diagnosis and treatments of CVID patients.

immunology↗

bioRxiv2021

RNA-seq, bioinformatic identification of potential MicroRNA-Like Small RNAs in the edible mushroom Agaricus bisporus and experimental approach for their validation

Although genomes from many edible mushrooms are sequenced, studies on fungal miRNAs are scarce. Most of the bioinformatic tools are designed for plants or animals but fungal miRNAs processing and expression share similarities and differences with both kingdoms. Moreover, since mushroom species such as Agaricus bisporus (white button mushroom) are frequently consumed as food, controversial discussions are still evaluating whether their miRNAs might or might not be assimilated, perhaps within extracellular vesicles (i.e exosomes). Therefore, the A. bisporus RNA-seq was studied in order to identify potential de novo miRNA-like small RNAs (milRNAs) that might allow their later detection in the diet. Results pointed to 1 already known and 37 de novo milRNAss. Three milRNAss were selected for RT-qPCR experiments. Precursors and mature milRNAs were found in the edible parts (caps and stipes) validating the predictions carried out in silico. When their potential gene targets were investigated, results pointed that mostly were involved in primary and secondary metabolic regulation. However, when human transcriptome is used as target, the results suggest that they might interfere with important biological processes related with cancer, infectious process and neurodegenerative diseases.

bioinformatics↗

bioRxiv2021

HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma

Ewing sarcoma (EWS) is an aggressive developmental sarcoma driven by a fusion gene, EWSR1-FLI1. However, little is known about the regulation of EWSR1-FLI1 chimeric fusion gene expression. Here, we demonstrate that active nuclear HDAC6 in EWS modulates acetylation status of specificity protein 1 (SP1), consequently regulating SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. Overexpression of HDAC6 in primary EWS tumor clinical samples correlates with a poor prognosis. Notably, a combination treatment of a selective HDAC6 inhibitor and doxorubicin (standard of care in EWS) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for EWS patients.

cancer biology↗

bioRxiv2020

Evidence for a role of phenotypic mutations in virus adaptation

Viruses interact extensively with the host molecular machinery, but the underlying mechanisms are poorly understood. Bacteriophage T7 recruits the small protein thioredoxin of the E. coli host as an essential processivity factor for the viral DNA polymerase. We challenged the phage to propagate in a host in which thioredoxin had been extensively modified to hamper its recruitment. The virus adapted to the engineered host without losing the capability to propagate in the original host, but no genetic mutations were fixed in the thioredoxin binding domain of the viral DNA polymerase. Virus adaptation correlated with mutations in the viral RNA polymerase, supporting that promiscuous thioredoxin recruitment was enabled by phenotypic mutations caused by transcription errors. These results point to a hitherto unknown mechanism of virus adaptation that may play a role in crossspecies transmission. We propose that phenotypic mutations may generally contribute to the capability of viruses to evade antiviral strategies.

evolutionary biology↗

bioRxiv2019

Pluripotency factors regulate the onset of Hox cluster activation in the early embryo

Pluripotent cells are a transient population present in the early mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while simultaneously suppressing lineage specification. Interestingly, these factors are not exclusive to uncommitted cells, but are also expressed during early phases of differentiation. However, their role in the transition from pluripotency to lineage specification is largely unknown. Using genetic models for controlled Oct4 or Nanog expression during postimplantation stages, we found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that the HoxB cluster is coordinately regulated in this way by OCT4 binding sites located at the 3 end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the pre-committed epiblast, but are also necessary for the proper deployment of subsequent developmental programs.

developmental biology↗