Biology subjects

Iglesias, A.

Publications and source records attributed to Iglesias, A..

8 recordsLinked to original sources

bioRxiv2026

SMARCA4 MUTATIONS PROMOTE CHEMOTHERAPY RESISTANCE IN T-ACUTE LYMPHOBLASTIC LEUKEMIA THROUGH ALTERED CHROMATIN REMODELING AT AP1-ASSOCIATED REGULATORY REGIONS

Chromatin remodelers play a critical role in orchestrating chemotherapy responses in cancer cells. Components of the SWI/SNF complex are frequently mutated across cancer types, with the ATPase subunit SMARCA4 among the most commonly altered. In T-cell acute lymphoblastic leukemia (T-ALL), however, SMARCA4 mutations are rare at diagnosis but enriched in relapse samples, suggesting a potential role in therapy resistance. Using isogenic T-ALL cell lines with or without SMARCA4 mutations, we show that mutant SMARCA4 confers resistance to a broad range of chemotherapeutic agents. By combining ATAC-seq and RNA-seq, we demonstrate that SMARCA4-mutant cells display an attenuated transcriptional response to chemotherapy accompanied by impaired remodeling of AP-1-associated regulatory regions linked to stress response. These cells downregulate stress-related genes while maintaining expression programs associated with cellular fitness. Pharmacological inhibition of AP-1 phenocopies this response, further supporting a functional link between SWI/SNF-mediated remodeling at AP-1-associated regulatory regions, AP-1 activity, and chemotherapy sensitivity. Together, our findings indicate that SWI/SNF-mediated remodeling of these regions contributes to an effective chemotherapy-induced stress response, and that its failure provides T-ALL cells with a survival

cancer biology↗

bioRxiv2026

Developmental programming of hematopoietic stem cell dormancy by evasion of Notch signaling

Dormant hematopoietic stem cells (HSCs) are a rare subset of deeply quiescent, metabolically inactive cells that preserve lifelong hematopoietic regeneration. In mice, these cells were thought to arise exclusively after birth in the BM, while fetal liver HSCs were considered uniformly proliferative and rapidly expanding. Here, using H2B-GFP label-retention strategies, we identify a previously unrecognized population of low-dividing HSCs that is specified during embryogenesis and persists into adulthood. We show that this dormant state is established in specific fetal HSCs that evade the activation of Notch signaling within the fetal liver niche, rather than through global loss of pathway activity. Genetic and transient perturbation of Notch signaling reveals a narrow developmental window in during which reduced Notch exposure promotes entry into a durable dormancy program, whereas irreversible pathway disruption compromises long-term function. Notably, transient Notch during fetal development, but not in adult BM, induces HSC quiescence while enhancing long-term repopulation capacity. Together, these findings demonstrate that HSC dormancy is developmentally programmed before birth and identify evasion of Notch signaling as a key mechanism establishing this state, fundamentally revising current models of how long-term regenerative potential is specified.

developmental biology↗

bioRxiv2025

Diverse transcriptomic and mutational patterns but limited functional pathway alterations in patient-derived SS cells

Structured AbstractO_ST_ABSBackgroundC_ST_ABSEradication of SS is hampered by its genetic and molecular heterogeneity. A better understanding of the putative commonalities underlying SS oncogenicity may help to provide more efficient therapeutic strategies against this devastating disease. PurposeThe present work analyzes the whole transcriptome of different patient-derived SS cells to identify expression patterns, functional programs and expressed gene mutations that may provide clues on new therapeutic options for SS patients MethodsMononuclear cells were recovered by Ficoll gradient separation from fresh peripheral blood of SS patients (n=7). Selected pathway-based compounds and the MALT1 inhibitor MI2 were used for in vitro drug sensitivity testing. SS cells viability was evaluated using CellTiter-Glo_3D Cell Viability Assay and flow cytometry analysis. We validated the usefulness of MI2 using patient-derived SS cells xenotransplanted (PDX) into Nod Scid Gamma mice. ResultsIn vitro data indicated that cell lines and primary malignant SS cells all display different sensitivities against specific pathway inhibitors. However, MALT1 inhibition led to a robust effect in vitro that was partially reproduced in the in vivo NSG mice xenograft model. ConclusionOur investigations revealed the actual possibility of inhibiting the downstream TCR signaling complex form by CARD11, BCL10 and MALT1 in SS therapy. Key PointsPatient-derived SS cells are transcriptionally and mutationally heterogeneous but share some common pathway alterations. Inhibition of MALT1 reduces NF-{kappa}B signaling and cell growth in cell lines and patient-derived SS cells.

cancer biology↗

bioRxiv2022

IκBα controls dormancy induction in Hematopoietic stem cell development via retinoic acid

Recent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-{kappa}B has been implicated in the development of HSCs. Here, we identify a chromatin binding function for I{kappa}B (also known as the inhibitor of NF-{kappa}B) that is Polycomb repression complex 2 (PRC2)-dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the I{kappa}B knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. I{kappa}B deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such as in vitro culture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the I{kappa}B - deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, I{kappa}B binding itself is found in the promoters of retinoic acid receptors rar in the AGM, and rar{gamma} in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of I{kappa}B-deficient AGMs leading to premature dormancy of LT-HSCs that persists in the FL LT-HSCs.

cell biology↗

bioRxiv2021

Solid state NMR reveals a parallel in register architecture for an infectious recombinant prion

Two alternative architectures have been proposed for PrPSc, the most notorious prion: a parallel in register {beta} stack (PIRIBS) and a 4-rung {beta}-solenoid (4R{beta}S). We challenged these two models by measuring intermolecular 13C-13C dipole-dipole couplings of 13CO-labelled Phe residues in a fully infectious sample of recombinant bank vole PrPSc (recBVPrPSc) using a PITHIRDS-CT solid state NMR (ssNMR) experiment. To our surprise, data strongly support a PIRIBS architecture. However, the mean distance measured ([~]6.5 [A]) suggests that a minimum of two of the three Phe residues are not perfectly stacked at the canonical [~]5 [A] cross-{beta} distance. Additional ssNMR experiments show some local conformational variability of the Phe residues within limits of a relatively high rigidity. The most parsimonious interpretation of our data is that recBVPrPSc is arranged as a PIRIBS, although additional conformers with alternative architectures cannot be excluded, including a mixture of PIRIBS and 4R{beta}S. Author summaryPrPSc is the most notorious prion. It is an infectious protein that cuases fatal neurodegenerative diseases in humans and animals. PrPSc is the aberrant version of a brain protein, PrPC. PrPSc and PrPC have the same prinary structure, but different secondary, tertiaty and quaternary structures. PrPSc is capable of templating PrPC to convert to the PrPSc conformation, which is the basis of its capacity to propagate. Two plausible structural models of PrPSc have been proposed, the four-rung {beta}-solenoid (4R{beta}S) and the parallel in-register {beta} stack (PIRIBS) model. In both cases the driving force of the templating mechanism consists of "sticky" surface {beta}-strands; however, in the PIRIBS model all the {beta}-strands that conform a PrPSc monomer lie flat on a surface whereas in the 4R{beta}S model they wind in a corkscrew fashion. Here, we analyzed fully infectious recombinant PrPSc using a solid state NMR technique, PITHIRDS, that allows probing distances between specific labelled amino acid residues. To our surprise (as we have defended the 4R{beta}S model in the past), results clearly show the presence of a PIRIBS structure in our sample.

biochemistry↗

bioRxiv2020

Structural features of an infectious recombinant PrPSc prion using solid state NMR

PrPSc, the first described and most notorious prion, is the only protein known to cause epidemics of deadly disease. Its properties are encoded in its unique structure. Here we report a first solid state NMR study of a uniformly labelled (U-13C,15N)-Bank vole (BV) infectious recombinant PrPSc prion. C-C, C-H and N-H spectra were obtained with MAS rotation of the sample at up to 60 kHz. We obtained amino acid-type secondary structure information and used it to challenge a physically plausible atomistic model of PrPSc consisting of a 4-rung {beta} solenoid recently proposed by us. In all cases, our model was compatible with the data. This study shows that elucidation of the structure of PrPSc is within reach using recombinant PrPSc, NMR, and our model as a guiding tool.

biochemistry↗

bioRxiv2020

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer's disease

We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimers disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.

genetics↗

bioRxiv2019

Out of the abyss: Genome and metagenome mining reveals unexpected environmental distribution of abyssomicins

Natural products have traditionally been discovered through the screening of culturable microbial isolates from all sort of environments. The sequencing revolution allowed the identification of dozens of biosynthetic gene clusters (BGCs) within single bacterial genomes, either from cultured or uncultured strains. However, we are still far from fully exploiting the microbial reservoir, as most of the species are non-model organisms with complex regulatory systems and yet recalcitrant to be engineered. Today, genomic and metagenomic data produced by laboratories worldwide covering the most different natural and artificial environments on Earth, are an invaluable source of raw information from which natural product biosynthesis can be accessed. In the present work, we describe the environmental distribution and evolution of the abyssomicin BGC through the analysis of publicly available genomic and metagenomic data. Our results demonstrate that the selection of a pathway-specific enzyme to direct the genome mining is an excellent strategy that led to the identification of 74 new Diels-Alderase homologs and unveiled a surprising prevalence of the abyssomicin BGC within terrestrial habitats, mainly soil and plant-associated, where we have identified five complete and 12 partial new abyssomicin BGCs and 23 new potential abyssomicin BGCs. Our results strongly support the potential of genome and metagenome mining as a key preliminary tool to inform bioprospecting strategies aiming at the identification of new bioactive compounds such as -but not restricted to-abyssomicins.

microbiology↗