Biology subjects

Perez, R. F.

Publications and source records attributed to Perez, R. F..

5 recordsLinked to original sources

bioRxiv2026

Replicative history as a major determinant of epigenetic noise across human tissues

DNA methylation changes accumulate with age through both regulated and stochastic processes, yet the determinants of epigenetic information loss remain poorly defined. Using genome-wide DNA methylation profiles from 1,531 healthy human samples spanning 14 tissues, we quantified epigenetic noise by Shannon entropy and corrected it for cellular and tissue heterogeneity. Adjusted entropy was consistently low in promoters, first exons and CpG islands, and high in CpG-poor and intergenic regions. Cumulative mitotic history showed a stronger association with epigenetic noise than chronological age, explaining most of its variance particularly within CpG-rich regulatory regions. By contrast, age-related, replication-independent effects predominated outside CpG islands and in low-proliferative tissues such as the brain. Moreover, biological age acceleration was largely attributable to cell division in a tissue-specific manner. Collectively, mitotic history emerges as a major determinant of epigenetic noise accumulation across human tissues, while genomic context modulates regional vulnerability to methylation information loss during aging.

genomics↗

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

Coordinated regulation of the metaboproteome by Hsp90 chaperones controls metabolic plasticity

Heat shock protein 90 (Hsp90) chaperones participate in the stabilization and activation of hundreds of proteins, thereby acting as signaling hubs. A mitochondrial subpopulation of Hsp90 has been previously described; however, little is known about its role in metabolism. Here, we showed that loss of individual Hsp90 isoforms differentially affects oxygen consumption and metabolic flexibility. Proteomic and metabolomic evaluation demonstrated that Hsp90 regulates the mitochondrial metabolic network, including respiration, fatty acid oxidation, and redox homeostasis. Loss of the mitochondrial chaperone TRAP1 induced compensatory binding of Hsp90s to TRAP1-dependent proteins, indicating a mechanism for the role of Hsp90 chaperones in metabolic reprogramming. When considered with previous findings, a temporal pattern of regulation emerges whereby Hsp90s control the transcription, translation, import, and assembly of mitochondrial protein complexes. Our findings expand the scope of Hsp90-regulated processes and potentially inform the effects of isoform-specific Hsp90 inhibitors on metabolic reprogramming in cancer and other diseases.

biochemistry↗

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↗