Biology subjects

Teixeira, J.

Publications and source records attributed to Teixeira, J..

13 recordsLinked to original sources

bioRxiv2026

Cldn18 evolution reveals pleiotropic constraints in vertebrate stomach loss

Understanding the origins of anatomical innovations is central to elucidate the evolution of phenotypic diversity, as novel body plans often underpin the colonization of new ecological niches. The stomach, with its acid-secreting glands, evolved in the gnathostome ancestor and has been lost repeatedly. Claudin 18 (CLDN18) is a tight-junction protein that preserves gastric epithelial integrity against extreme H gradients and, in mammals, also acts in the lung through alternative first-exon isoforms. This dual role suggests that pleiotropy may shape the fate of CLDN18 after stomach loss. Here, we provide a detailed analysis of CLDN18 evolution across jawed vertebrates. CLDN18 originated in the gnathostome ancestor and is expressed in the stomach of elasmobranchs. We found no evidence of the gene in chimaeras or lungfishes, two additional agastric lineages, extending the loss of cldn18a previously described in agastric teleosts. Exon 1 architecture indicates a tandem duplication in the Euteleostomi ancestor, whereas stomach- and lung-associated isoforms are partitioned in most tetrapods examined. Monotremes, although agastric, retain only the lung-associated exon 1, consistent with lung function sustaining selection on the locus. Together, these findings reveal a complex evolutionary history involving gene loss, alternative splicing, tissue-specific regulation, and secondary exon loss, highlighting how pleiotropy and regulatory partitioning shaped the evolution of epithelia in jawed vertebrates.

evolutionary biology↗

bioRxiv2026

Identification of UCB-9721 as a potent inhibitor of MyoA, the essential class XIV myosin motor of apicomplexan parasites

The virulence of Toxoplasma gondii and other apicomplexan parasites relies on a unique form of cellular motility driven by MyoA, an unconventional class XIV myosin motor protein. To identify new chemical probes for investigating the molecular mechanisms of parasite motility, we screened over 50,000 small molecules for inhibitors of T. gondii MyoA (TgMyoA). The top hit from the screen, UCB-9721, is almost 40-fold more potent as an inhibitor of TgMyoA actin-activated ATPase activity than the previously described TgMyoA inhibitor, KNX-002, and 45-fold more potent at inhibiting parasite motility, with no detectable toxicity towards mammalian cells. UCB-9721 also inhibited the motility and/or growth of the related apicomplexan parasites Plasmodium falciparum, Cryptosporidium parvum, and Babesia duncani, suggesting that this compound will be a useful new chemical probe for studying motility and MyoA function in apicomplexan parasites more broadly. While UCB-9721 and KNX-002 were identified independently, they share a similar chemical scaffold. To determine why UCB-9721 is so much more potent than KNX-002 and to inform future development of this inhibitor class, we undertook comparative molecular docking analyses, targeted TgMyoA mutagenesis, and a directed structure-activity relationship analysis. The results identified the sulfonamide group of UCB-9721 and its hydrogen bond interactions with R249, E275 and a stabilized water network within the TgMyoA binding pocket as key to the compounds increased potency. Further development of UCB-9721, informed by the results presented here, may transform this promising new chemical class into actionable drug development leads against this important group of human and animal pathogens.

microbiology↗

bioRxiv2026

A dual-phase enhancer couples progenitor maintenance and pancreatic lineage stability

Enhancers orchestrate transcriptional programs that control organ development and maintain differentiated cell states, yet how individual enhancers integrate developmental and long-term tissue maintenance logic remains poorly understood. Here, we identify a distal enhancer downstream of ptf1a (z3-DpE) as a regulatory node coupling pancreatic development with acinar cell homeostasis in zebrafish. Deletion of z3-DpE reduces ptf1a expression in pancreatic multipotent progenitor cells (MPCs), leading to depletion of the progenitor pool, altered morphogenesis, and premature exocrine differentiation. Transcriptomic analysis reveals broad repression of proliferation- and morphogenesis-related genes, including Notch pathway components essential for progenitor maintenance. After differentiation, loss of z3-DpE contributes to acinar cell loss, expansion of ductal and endocrine compartments, and disrupted pancreatic architecture. Chromatin-accessibility profiling of purified acinar cells reveals that reduced ptf1a activity leads to widespread remodeling of the acinar chromatin landscape, with decreased accessibility at loci associated with acinar identity and developmental programs, and increased accessibility at sites linked to inflammation, epithelial plasticity, and pancreatic cancer susceptibility. Histopathological analysis shows disorganized acinar tissue with increased duct-like structures and mucinous lesions reminiscent of early pancreatic neoplasia. Thus, z3-DpE safeguards acinar identity by sustaining ptf1a expression and a chromatin landscape that restricts fate instability and pathological plasticity. Our findings demonstrate the mechanistic sufficiency of a single enhancer to coordinate progenitor expansion and long-term lineage stabilization, providing a paradigm for how a developmental regulatory element is redeployed to preserve tissue integrity and suppress disease-associated plasticity.

developmental biology↗

bioRxiv2025

Extracellular matrix mechanical cues (dys)regulate metabolic redox homeostasis due to impaired autophagic flux

Extracellular matrix (ECM) stiffness is increasingly recognized as a critical regulator of cellular behavior, governing processes such as proliferation, differentiation, and metabolism. Neurodegenerative diseases are characterized by mitochondrial dysfunction, oxidative stress, impaired autophagy, and progressive softening of the brain tissue, yet research into how mechanical cues influence cellular metabolism in this context remains scarce. In this study, we evaluated the long-term effects of brain-compliant, soft ECM on mitochondrial bioenergetics, redox balance, and autophagic capacity in neuronal cells. Using human neuroblastoma (SH-SY5Y) and mouse hippocampal (HT22) cell lines, as well as primary mouse neurons, we observed that prolonged exposure to soft ECM resulted in mitochondrial bioenergetic dysfunction, redox imbalance, and disrupted autophagic flux. These findings were consistently validated across both human and mouse neuronal cells. Our data indicate a decreased maximal autophagic capacity in cells exposed to long-term soft ECM, potentially due to an imbalance in autophagosome formation and degradation, as demonstrated by decreased LC3 II levels following chloroquine-induced autophagic flux inhibition. This impairment in autophagy was coupled with increased cellular oxidative stress, further indicating metabolic alterations. These findings emphasize the critical role of ECM stiffness in regulating neuronal cell metabolism and suggest that prolonged exposure to soft ECM may mimic key aspects of neurodegenerative disease pathology, thereby enhancing the physiological relevance of in vitro models. This study underscores the necessity for further research into ECM mechanics as a contributing factor in neurodegenerative disease progression and as a potential target for therapeutic strategies.

cell biology↗

bioRxiv2024

The plant pioneer factor LFY uses trans-kingdom chromatin remodeling mechanisms in vertebrates

Multicellular complexity is thought to have evolved independently in animals and plants, but the molecular constraints driving this complexity are poorly understood. Genetic networks activated during animal and plant development both involve the regulation of nucleosome occupancy by chromatin remodelers. Pioneer factors, often specific to plants or animals, bind to nucleosome-occupied DNA in a sequence-specific manner, recruiting chromatin remodelers to control lineage-specific genetic networks. In this study, a plant-specific pioneer factor, LFY, when expressed in zebrafish cells, recruits the vertebrate chromatin remodeler Smarca4a to make DNA accessible at LFY binding sites. This allows a plant LFY-controlled promoter, introduced into the zebrafish genome, to become transcriptionally active in a Smarca4a-dependent manner. Our findings suggest that the protein-protein interaction between pioneer factors and chromatin remodelers is a trans-kingdom mechanism likely reflecting ancient eukaryotic events that became a key evolutionary constraint in the path to biological complexity.

evolutionary biology↗

bioRxiv2024

Metabolic and age-associated epigenetic barriers during direct reprogramming of mouse fibroblasts into induced cardiomyocytes

Heart disease is the leading cause of mortality in developed countries novel regenerative procedures are warranted for improving patients well fare. Direct cardiac conversion (DCC) can create induced cardiomyocytes (iCMs) and besides holding great promise, lacks clinical effectiveness for cardiac regeneration as metabolic and age-associated barriers remains elusive. Here, we identify by histone post-translational analysis that DCC triggers major age-dependent alterations in the epigenetic landscape. Metabolomics revealed decrease abundance of anabolic metabolites related to TCA cycle and glutaminolysis and profound mitochondrial network remodeling, with increased elongation and interconnectivity and reliance in mitochondrial respiration in iCMs. Importantly, adult-derived iCMs present increase accumulation of oxidative stress in the mitochondria and pharmacological activation of mitophagy increase DCC of adult fibroblasts in vitro. Metabolic modulation in vitro and dietary manipulations in vivo improves DCC efficiency and are accompanied by significant alterations in the histone acetylation and methylation landscape and mitochondria homeostasis. Our study provides evidence that metaboloepigenetics as a direct role in cell fate transitions driving direct cardiac conversion into iCMs, highlighting the potential use of metabolic modulation in increasing cardiac regenerative strategies.

cell biology↗

bioRxiv2023

Unravelling the regulatory function of a short 3'UTR sequence in zebrafish and in human cells

The mechanisms of gene expression regulation are essential for cell identity and function, and their disruption usually leads to human disease. The 3 untranslated region (UTR) of mRNA contains important regulatory elements of gene expression, including upstream sequence elements (USEs) that are cis-regulatory sequences localized upstream of polyA signals (PAS). One of the best functionally characterised USEs is located in the 3UTR of the Drosophilas polo gene, which disruption leads to critical phenotypes in adult flies. In this work we found that the USE of the Drosophilas polo gene (DplUSE) is also found in in the 3UTR of vertebrate genes, including zebrafish, mouse and human genes, showing higher levels of conservation than the whole 3UTR sequence. Using reporter assays, we show that DplUSE is able to increase gene expression in vitro in human cell lines and in vivo in zebrafish embryos. Importantly, in humans, the DplUSE containing genes are enriched for genes associated to serious diseases such as Congenital abnormalities and Malignant neoplasms, illustrating the potential of this sequence to modulate genes with relevant biological functions and related with human health. Concomitantly, when sequestering the molecular machinery that operates at the DplUSE using a dominant negative strategy, we show that this is enough to dysregulate DplUSE containing genes in human cells and disrupt proper embryo development in zebrafish. Aiming to understand the molecular mechanism operating at the DplUSE, we identified three RNA binding proteins (RBP) that specifically bind to the DplUSE in vertebrates. Importantly, one of such RBPs is PTBP1, the vertebrate orthologue of the fruit flys RBP Heph, that was demonstrated to be required for the DplUSE function in Drosophila. To test if PTBP1is essential for the DplUSE function, as observed in Drosophila, we depleted PTBP1 from human cells and observed a downregulation of the expression of DplUSE containing genes, demonstrating that the molecular mechanisms that operate at DplUSE are ultra-conserved. Finally, we explored if variants in DplUSE consensus could be associated to human disease. We found a reported single nucleotide polymorphism (SNP; rs3087967) that is associated with malignant tumor of colon and generates an ectopic consensus of DplUSE in the 3 UTR of the tumorigenic POU2AF2/C11orf53 gene. We further show that this ectopic DplUSE motif causes a gain-of-function in vivo in zebrafish gut cells, suggesting its involvement in colon cancer development. These results show that a short motif present in the 3UTR of genes from phylogenetically distant bilaterians, from fruit flies to humans, control genes expression through an ultra-conserved mechanism involving RBPs binding and its dysregulation might impact in human disease.

molecular biology↗

bioRxiv2023

FOXM1 expression reverts aging chromatin profiles through repression of the senescence-associated pioneer factor AP-1

Aging is characterized by changes in gene expression that drive deleterious cellular phenotypes leading to senescence. The transcriptional activation of senescence genes has been mainly attributed to epigenetic shifts, but the changes in chromatin accessibility and its underling mechanisms remain largely elusive in natural aging. Here, we profiled chromatin accessibility in human dermal fibroblasts (HDFs) from neonatal and octogenarian individuals. We found that AP-1 binding motifs are prevalent in elderly specific accessible regions of the chromatin while neonatal-specific regions are highly enriched for TEAD binding motifs. We further show that TEAD4 and FOXM1 share a conserved transcriptional regulatory landscape controlled by an age-dependent enhancer that closes with aging and drives senescence when deleted. Finally, we demonstrate that FOXM1 ectopic expression in elderly cells partially resets chromatin accessibility to a youthful state due to FOXM1 repressive function in the promoters of several members of the AP-1 complex. These results place FOXM1 at a top hierarchical level in chromatin remodeling required to prevent senescence.

genetics↗

bioRxiv2021

RNA nucleotide repeats induce mitochondrial dysfunction and the ribosome associated quality control

Nucleotide repeat sequences are prevalent in the genome and expansion of these sequences is associated with more than 40 neuromuscular disorders. To understand the pathogenic mechanisms underlying RNA-repeat toxicity, we performed a genetic screen in a Caenorhabditis elegans model expressing an expanded CUG repeat specifically in the muscle. Here, we show that expression of this RNA repeat impairs motility by mitochondrial dysfunction, disrupting mitochondrial morphology and respiration. The phenotype is dependent on the RNA-binding factor MBL-1 and requires factors from the ribosome-associated protein quality control complex. Furthermore, Coenzyme Q supplementation rescued the motility impairment and all of the mitochondrial phenotypes. Together, our data reveal the importance of mitochondrial dysfunction in the molecular pathogenesis of RNA repeat expansion disorders.

genetics↗

bioRxiv2021

RNA interference mediates RNA toxicity with parent-of-origin effects in C. elegans expressing CTG repeats

Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases. These repeats cause RNA toxicity and trigger multisystemic symptoms that worsen with age. RNA toxicity can trigger, through an unclear mechanism, severe disease manifestation in infants that inherited repeats from their mothers. Here we show in Caenorhabditis elegans how RNA interference machinery causes intergenerational toxicity through inheritance of siRNAs derived from CUG repeats. The maternal repeat-derived small RNAs cause transcriptomic changes in the offspring, reduce motility and shorten lifespan. However, the toxicity phenotypes in the offspring can be rescued by perturbing the RNAi machinery in affected mothers. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring and causes disease phenotypes through intergenerational epigenetic inheritance.

molecular biology↗

bioRxiv2020

Cis-regulatory similarities in the zebrafish and human pancreas uncover potential disease-related enhancers

Introductory paragraphThe pancreas is a central organ for human diseases that have a dramatic societal burden, such as pancreatic cancer and diabetes1,2. Non-coding cis-regulatory elements (CREs) of DNA control gene expression3,4, being required for proper pancreas function. Most disease-associated alleles5,6 are non-coding, often overlapping with CREs5, suggesting that alterations in these regulatory sequences contribute to human pancreatic diseases by impairing gene expression. However, functional testing of CREs in vivo is not fully explored. Here we analysed histone modifications, transcription, chromatin accessibility and interactions, to identify zebrafish pancreas CREs and their human functional equivalents, uncovering disease-associated sequences across species. We found a human pancreatic enhancer whose deletion impairs the tumour suppressor gene ARID1A expression, conferring a potential tumour suppressor role to this non-coding sequence. Additionally, we identified a zebrafish ptf1a distal enhancer which deletion generates pancreatic agenesis, demonstrating the causality of this condition in humans7 and the interspecies functional equivalency of enhancers.

genomics↗

bioRxiv2020

Selection and subsequent physiological characterisation of industrial Saccharomyces cerevisiae strains during continuous growth at sub- and- supra optimal temperatures

A phenotypic screening of 12 industrial yeast strains and the well-studied laboratory strain CEN.PK113-7D at cultivation temperatures between 12 {degrees}C and 40 {degrees}C revealed significant differences in maximum growth rates and temperature tolerance. Two Saccharomyces cerevisiae strains, one performing best at sub-, and the other at supra-optimal temperatures, plus the laboratory strain, were selected for further physiological characterization in well-controlled bioreactors. The strains were grown in anaerobic chemostats, at a fixed specific growth rate of 0.03 h-1 and sequential batch cultures at 12, 30, and 39 {degrees}C. We observed significant differences in biomass and ethanol yields on glucose, biomass protein and storage carbohydrate contents, and biomass yields on ATP between strains and cultivation temperatures. Increased temperature tolerance coincided with higher energetic efficiency of cell growth, indicating that temperature intolerance is a result of energy wasting processes, such as increased turnover of cellular components (e.g. proteins) due to temperature induced damage.

physiology↗

bioRxiv2017

Evolutionary Genetics of a Disease Susceptibility Locus in CDHR3

Selective pressures imposed by pathogens have varied among human populations throughout their evolution, leading to marked inter-population differences at some genes mediating susceptibility to infectious and immune-related diseases. A common polymorphism resulting in a C529 versus T529 change in the Cadherin-Related Family Member 3 (CDHR3) receptor is associated with rhinovirus-C (RV-C) susceptibility and severe childhood asthma. Given the morbidity and mortality associated with RV-C dependent respiratory infections and asthma, we hypothesized that the protective variant has been under selection in the human population. Supporting this idea, a recent cross-species outbreak of RV-C among chimpanzees in Uganda, which carry the ancestral risk allele at this position, resulted in a mortality rate of 8.9%. Using publicly available genomic data, we sought to determine the evolutionary history and role of selection acting on this infectious disease susceptibility locus. The protective variant is the derived allele and is found at high frequency worldwide, with the lowest relative frequency in African populations and highest in East Asian populations. There is minimal population structure among haplotypes, and we detect genomic signatures consistent with a rapid increase in frequency of the protective allele across all human populations. However, given strong evidence that the protective allele arose in anatomically modern humans prior to their migrations out of Africa and that the allele has not fixed in any population, the patterns observed here are not consistent with a classical selective sweep. We hypothesize that patterns may indicate frequency-dependent selection worldwide. Irrespective of the mode of selection, our analyses show the derived allele has been subject to selection in recent human evolution.

genetics↗