Biology subjects

Fraga, M. F.

Publications and source records attributed to Fraga, M. F..

7 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↗

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

Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.

cell biology↗

bioRxiv2017

Non-canonical aberrant DNA hypermethylation in glioma

Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC in primary samples from 54 gliomas and 72 colorectal cancer patients. Levels of 5hmC in colorectal cancer were very low and no consistent changes were detected between control tissues and tumors. As expected, levels of 5hmC in non-tumoral brain samples were high and significantly reduced at the 49,601 CpG sites in gliomas. Strikingly, hypo-hydroxymethylation at 4,627 (9.3%) of these CpG sites was associated with aberrant DNA hypermethylation. The DNA regions containing these CpG sites were enriched in H3K4me2, and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. We conclude that this data identifies a novel 5hmC-dependent non-canonical class of aberrant DNA hypermethylation in glioma.

cancer biology↗