Biology subjects

Fernandez, A. F.

Publications and source records attributed to Fernandez, A. F..

7 recordsLinked to original sources

bioRxiv2026

Au_Sus: A tiered consensus census of human autophagy genes

Autophagy is a critical cellular process, yet its genomic definition remains inconsistent across digital repositories. This lack of standardisation hinders reproducibility in high-throughput studies and clinical research. Here, we present Au_Sus, a high-confidence human autophagy census established through a frequency-based majority consensus of seven primary databases and literature sources. After rigorous manual curation and nomenclature standardisation, we defined a tiered framework: Maxim_Au (2,581 genes), Au_Sus (the 201-gene core consensus), and Minim_Au (77 universal genes). Functional enrichment and protein-protein interaction analysis confirm that Au_Sus captures a highly integrated and purified autophagic machinery, with significant associations to neurodegeneration and oncology. Furthermore, an analysis of nearly 100 published cancer gene signatures revealed profound functional dilution, with 60% of signature genes absent from our consensus. These findings suggest that many of these models incorporate peripheral stress markers rather than core autophagic effectors. Hence, Au_Sus (freely accessible at ausis.uniovi.es) provides a reliable, ready-to-use benchmark to standardise the study of autophagy in health and disease.

cell biology↗

bioRxiv2026

Repetitive DNA-resolved epigenomics maps chromatin rewiring during aging and malignant transformation

Repetitive DNA constitutes more than half of the human genome, yet its chromatin landscape remains poorly understood. Here, we integrated multi-mapping reads across 3, 744 repeat subfamilies and 937 ChIP-seq experiments for six canonical histone marks in hematopoietic cells and chronic malignancies from the BLUEPRINT consortium. Chromatin signals at repeats encode cell type-specific signatures, with certain elements (Alu, SVA, ERV/Gypsy LTRs) exhibiting conserved epigenomic profiles distinct from surrounding single-copy sequences, and LTRs acting as chromatin boundaries. Combinatorial analyses further revealed five major repeat epitypes (promoter-like, active/poised enhancers, and two heterochromatin domains) that enhance annotations from uniquely-mapping reads. Beyond constitutive heterochromatin, we uncovered a highly plastic heterochromatin characterized by concurrent H3K36me3 and H3K9me3 that can dynamically switch to active epitypes in B-cell chronic neoplasms. Although malignant transformation involved global loss of histone marks across repeats, we identified targeted heterochromatinization of satellites and LTRs, mirroring changes in aged B cells, and gains of active marks at CD34 enhancers and disease-related genes. Likewise, aging primes the heterochromatin landscape toward malignancy but still requires de novo acquisition of active marks at regulatory regions to promote transformation. Our atlas provides the most comprehensive resource for dissecting chromatin dynamics at repetitive DNA in hematopoietic aging and cancer.

molecular biology↗

bioRxiv2025

ATG4D loss leads to late-onset cardiomyopathy and stress-induced heart failure in mice, and its repression marks maladaptive cardiac remodeling in humans

In the last years, autophagy has emerged as an essential pathway for most cellular functions. Basal autophagy plays a protective role as a quality control mechanism by which damaged or noxious cellular components are degraded and cellular organelles are periodically renewed. Moreover, autophagic activity can be increased in situations of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, or the presence of intracellular pathogens. Normally, induction of autophagy is protective, although in some circumstances, such as conditions of hemodynamic stress, autophagosome accumulation upon autophagy induction can be a maladaptive process. The deficiency of the autophagic protease ATG4D in mice leads to the accumulation of cellular autophagosomes in most tissues, including the heart. Here, we show that the increased autophagosome content of atg4d-/- mice is linked to the development of late-onset cardiomyopathy and to increased susceptibility to heart failure induced by transverse aortic constriction. Furthermore, we report the existence of human ATG4D variants associated with cardiovascular pathologies and also that ATG4D expression is reduced in human obstructive hypertrophic cardiomyopathy and dilated cardiomyopathy, which highlights a conserved cardio-protective role of the ATG4D protease.

pathology↗

bioRxiv2024

Age-Dependent Maturation and Rejuvenation of the Neural 3D Chromatin Interactome in Enriched Environments

Aging is a multifactorial biological process resulting in physiological and cellular decline. However, our understanding of age-related changes in 3D genome organization and the effect of external interventions on this process, remains limited. Here we describe alterations in the landscape of the 3D chromatin interactome upon aging, utilizing the low input Promoter Capture Hi-C (liCHi-C) technique with hippocampal neurons. We integrated liCHi-C data with RNA-seq data to identify functional implications. Furthermore, we assessed the effect of exposure to environmental enrichment (EE). Remarkably, our results demonstrated an age- dependent modulation of promoter interactions and expression with EE, with aging-like changes induced in young mice upon EE, likely associated with early brain maturation; while age-related alterations were reverted in old mice, leading to a partial rejuvenation of aged mouse hippocampi. These findings revealed a dynamic behaviour of the neuronal 3D chromatin structure over time, which can be modulated by external interventions.

genomics↗

bioRxiv2024

A universal limit for mammalian lifespan revealed by epigenetic entropy

Loss of epigenetic information has been proposed as a potential driver of mammalian aging. However, its contribution to the well-documented variation in lifespan estimates among mammals remains to be elucidated. In this study, we examined DNA methylation entropy patterns at evolutionarily conserved CpG sites across multiple mammalian species to quantify age-associated epigenetic information loss. We found that longer-lived species tend to accumulate fewer CpGs exhibiting increased methylation noise over time, irrespective of whether these changes arise from hyper- or hypomethylation mechanisms. Importantly, the rate of epigenetic entropy gain declines in a linear fashion with species maximum lifespan, pointing to the existence of a universal constraint on mammalian longevity, estimated to lie in the vicinity of 220 years. We further demonstrated that this relationship and its associated limit were independent of species and sample selection, as well as phylogenetic relatedness, and remained robust across different scenarios of lifespan estimation uncertainty. Collectively, this work highlights the maintenance of epigenetic information as a key factor in explaining lifespan differences among species and proposes a universal maximum limit to natural mammalian longevity.

molecular biology↗

bioRxiv2023

A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma

BackgroundSarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumors do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumor growth. MethodsWe developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n=6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumor potential of IDH mutations found in two chondrosarcoma cases was analyzed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FindingsWe treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumor growth. Enasidenib induced a profound remodeling of the transcriptomic landscape not associated to changes in the 5mC methylation levels and its anti-tumor effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. InterpretationOverall, this work provides the first preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FundingSpanish Research Agency (grants PID2019-106666RB-I00; PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057). RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSSarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. The genomic nature of most sarcoma subtypes, displaying high inter- and intra-tumor heterogeneity with few recurrent driver mutations in a small portion of patients, makes these tumors especially indicated for personalized treatment approaches. For optimal development of these personalized protocols and a more efficient translation to the clinic, it is necessary to create patient-derived models suitable for testing the efficiency of candidate therapies. These strategies might be especially indicated for chondrosarcomas, a subtype of bone sarcoma that is inherently resistant to current therapies. Added value of this studyTo develop a personalized medicine strategy for sarcomas we have applied targeted sequencing protocols to detect druggable mutations in a collection of sarcomas cases with available patient-derived models. Among those potential druggable alterations detected in patient samples and avatar cell lines, we found IDH mutations in two chondrosarcomas. The presence of mutated IDH enzymes results in the accumulation of the oncometabolite 2-HG which contributes to driving tumor growth. In vitro and in vivo experiments evidenced the anti-tumor potential of the IDH mutant inhibitor enasidenib for the treatment of IDH2 mutant chondrosarcomas. Our transcriptomic and epigenomic analyses show that the mechanism of action of this drug is associated with the repression of proliferative pathways rather than with the promotion of tumor differentiation. Implications of all the available evidenceThis study suggests that enasidenib may represent an efficient therapeutic alternative for mutant IDH2 chondrosarcomas. This anti-proliferative mechanism of action of this drug may be especially relevant in dedifferentiated chondrosarcomas where reversal of this phenotype is not possible. In addition, this work provides support for the use of sarcoma patient-derived lines as avatar models capable of predicting (pre)-clinical responses in personalized medicine strategies.

cancer biology↗

bioRxiv2022

Autophagy alterations in white and brown adipose tissues of mice exercised under different training protocols

Autophagy is a conserved catabolic process that promotes cellular homeostasis and health. Although exercise is a well-established inducer of this pathway, little is known about the effects of different types of training protocols on the autophagy levels of tissues that are tightly linked to the obesity pandemic (like brown adipose tissue) but not easily accessible in humans. Here, we take advantage of animal models to assess the effects of short- and long-term resistance and endurance training in both white and brown adipose tissue, reporting distinct alterations on autophagy proteins LC3B and p62. For instance, both short-term endurance and resistance training protocols increased the levels of these proteins in white adipose tissue before this similarity diverges during long training, while autophagy regulation appears to be far more complex in brown adipose tissue. Additionally, we also analyzed the repercussion of these interventions in fat tissues of mice lacking autophagy protease ATG4B, further assessing the impact of exercise in these dynamic, regulatory organs (which are specialized in energy storage) when autophagy is limited. In this regard, only resistance training could slightly increase the presence of lipidated LC3B, while p62 levels increased in white adipose tissue after short-term training but decreased in brown adipose tissue after long-term training. Altogether, our study suggests an intricated regulation of exercise-induced autophagy in adipose tissues that is dependent on the training protocol and the autophagy competence of the organism.

molecular biology↗