Biology subjects

Toiber, D.

Publications and source records attributed to Toiber, D..

8 recordsLinked to original sources

bioRxiv2026

A systematic evaluation of SIRT6 as transcriptomic biomarker of aging

SIRT6 is a NAD+-dependent sirtuin that plays central roles in chromatin regulation, DNA repair, telomere maintenance, metabolic homeostasis, and inflammatory control. Although SIRT6 have long been implicated in aging because of its association with several hallmarks of aging, the available evidence remains largely context-dependent and mechanistic, limiting the interpretation of SIRT6 as a robust and evolutionarily conserved biomarker of aging. To comprehensively investigate the role of SIRT6 as an aging biomarker, we established SIRT6.db, a multi-species transcriptomic resource that integrates SIRT6-targeted perturbation experiments across diverse biological systems and organisms form all available SIRT6-related publications collected via a large-scale textual analysis of the SIRT6 literature using topic modeling. Based on this database, we identified both species-specific and evolutionarily conserved transcriptional and functional signatures associated with SIRT6 perturbation and established their relevance to hallmarks of aging. We showed that SIRT6 expression is generally stable during normal aging, but becomes dysregulated in Alzheimer's disease in cell type and stage-specific manner, highlighting the context dependence of its potential as a transcriptomic biomarker of aging.

bioinformatics↗

bioRxiv2026

SPARK-ID: Dynamic DSB-sensor interactomes reveal modular nuclear repair networks coordinated by connector proteins

DNA double-strand breaks (DSBs) activate repair pathways that must be coordinated with other cellular functions. Although DSB sensors SIRT6, Ku80, and MRE11 initiate repair, how they organize these nuclear processes remains unknown. SPARK-ID is a proximity-labeling strategy mapping DDR interactome dynamics. Using these sensors as baits, we resolved chromatin-associated interactomes from damage formation to recovery. The sensors shared an enriched repair core while capturing distinct interactors, allowing temporal specialization: SIRT6ID was biased toward RNA and chromatin regulation, Ku80ID toward telomere-associated and translational programs, and MRE11ID toward recombination and DNA synthesis. Modularity analysis showed these functions are organized into modules linked by "connectors". Among them, Nucleolin linked DNA repair, RNA-metabolism, and nucleolar modules. Nucleolin depletion rewired DSB-sensor interactomes, altered repair-associated complex composition, expanded {gamma}H2AX domains, and reduced BRCA1, 53BP1, and phospho-ATM foci. Altogether, SPARK-ID reveals modular DSB-sensor interactomes whose robustness depends on connectors that integrate and constrain the DNA damage response. Graphical AbstractThree DSB sensors (MRE11, Ku80, SIRT6) orchestrate DNA repair through dynamic protein-protein interaction networks that expand upon DSB induction. Proximity labeling reveals distinct sensor interactomes that share a functional core of nuclear processes while incorporating sensor-specific interactors for pathway specialization. These networks contain connector nodes that coordinate multiple parallel nuclear functions, enabling functional diversification and conferring robustness to the DNA damage response. The sensors reshape their interactome structure and composition to integrate and constrain cellular responses through organized macromolecular complexes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/740882v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1bb112dorg.highwire.dtl.DTLVardef@64cc4dorg.highwire.dtl.DTLVardef@1a0e2d1org.highwire.dtl.DTLVardef@18b3e8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Aging in Fast-Forward: An Inducible SIRT6 Deficiency model as a Lens on Brain Aging and Neurodegeneration

Aging and neurodegeneration occur gradually, making in vitro modeling challenging and costly. We generated a time-resolved, reversible neuron-like aging model by gradually depleting SIRT6. Within three weeks, their transcriptomes recapitulated brain-aging signatures and hallmarks. RNA-seq revealed clusters of nonlinear changes and predicted oscillatory DNA-damage and apoptotic programs, allowing stress response and adaptation. SIRT6 loss led to nuclear envelope breakdown and micronuclei accumulation, resembling accelerated-aging phenotypes. Some defects could be rescued by re-expressing SIRT6. As a tool for discovery, we uncovered disrupted nucleocytoplasmic transport as an aging pathway shared with neurodegenerative disorders. When SIRT6 depletion reached 30 days, transcriptional changes correlated with those in Alzheimers patients, but reversed after SIRT6 re-expression. Pathways associated with shSIRT6 and healthy aging became anticorrelated with AD, pointing to critical signatures. Our affordable and easy-to-use model captures key molecular features of aging, distinguishes physiological from disease-linked changes, and accelerates mechanistic discovery in a controllable, neuron-based system. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/705977v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@181c9d1org.highwire.dtl.DTLVardef@1e8be3dorg.highwire.dtl.DTLVardef@121d345org.highwire.dtl.DTLVardef@1b5589e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO A Novel Reversible Cellular Model of Gradual SIRT6 Decline Reveals Transcriptomic Transitions from Aging to Neurodegeneration. (1) We developed a neuron-like cellular system with gradual, inducible SIRT6 depletion to mimic the aging process. The model enables: (2) Recapitulation of hallmark features of aging, including genomic instability, cellular stress, and nuclear integrity loss. (3) Identification of novel SIRT6-regulated pathways, including impaired nucleocytoplasmic transport. (4) Clustering of dynamic, non-linear gene expression trajectories. (5) Distinction between reversible and irreversible changes following SIRT6 re-expression. (6) Transcriptomic comparison with human brain aging and AD revealing divergence points between healthy and pathological aging. C_FIG

molecular biology↗

bioRxiv2025

The Divergent 3D Genome Landscapes of Aging and Neurodegenerative mouse models

Chromatin structure is essential for gene regulation and genome stability, and neurons must preserve their 3D genome organization throughout life. This structure gradually deteriorates with aging and is further disrupted in neurodegenerative diseases. To investigate whether aging and neurodegeneration share early chromatin changes or diverge, we performed Hi-C on cortical neurons from adult, aged, and brain-specific SIRT6-knockout (S6-KO) mice, and compared them to the CK-p25 Alzheimers disease model results stratified by {gamma}H2AX levels. All models showed early features such as weakened interactions between chromosomes in expanded nuclei, A-to-B compartment shifts, and loss of architectural loops. However, aged neurons retained TAD prominence, short-range interactions, and enhancer-promoter loops, while pathological models showed reduced TAD prominence, shorter loops, and disorganized A-B mixing. These changes correlate with increased DNA damage. Our findings suggest that aging represents a "primed" state, where chromatin regulation begins to erode, but further stressors like DNA damage are associated with progression toward neurodegenerative breakdown.

molecular biology↗

bioRxiv2023

optimalTAD: annotation of topologically associating domains based on chromatin marks enrichment

In many eukaryotes, chromosomes are organized as strings of spatially segregated Topologically Associating Domains (TADs), characterized by a substantially increased frequency of interactions within them. Boundaries of TADs are highly enriched in histone acetylation chromatin marks and occupied binding sites of architectural proteins, highlighting the functional role of TADs in the regulation of gene expression. While many computational approaches have been developed for TAD identification, it remains challenging because of their nested structure, resulting in weakly overlapping sets of TADs at different scales. Here, we propose a novel algorithm optimalTAD for identifying the optimal set of TADs based on epigenetic marks enrichment. Assuming that the most dramatic enrichment corresponds to the best annotation of TAD boundaries, our algorithm optimizes TAD calling parameters by maximizing the difference in chromatin mark levels between TADs and their boundaries. Using this algorithm, we annotated TADs in multiple publicly available fruit fly and mammalian Hi-C datasets and identified a set of epigenetic marks that are best suited for TAD prediction. Through the analysis of diverse organisms and cell types with distinct underlying principles of TAD organization, we have shown that optimalTAD is a universal tool suitable for studying TAD structure, functions, and properties unique to specific cell types and organisms. optimalTAD is freely available at GitHub: https://github.com/cosmoskaluga/optimalTAD. Key PointsO_LIWe assume that the most dramatic enrichment of epigenetic marks corresponds to the best annotation of TAD boundaries. C_LIO_LIOur algorithm optimizes TAD calling parameters by maximizing the difference in chromatin mark levels between TADs and their boundaries. C_LIO_LIoptimalTAD is a universal tool that is applicable for studying TAD characteristics in diverse organisms and cell types. C_LIO_LIoptimalTAD enables the identification of a specific set of epigenetic marks that are most suitable for annotating TADs. C_LI

bioinformatics↗

bioRxiv2022

SIRT6 is a key regulator of mitochondrial function in the brain

SIRT6 is implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. In this work, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mice brains. Our analysis revealed that SIRT6 is a critical regulator of mitochondrial activity in the brain. In its absence, there is a mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolites content. We predict that SIRT6 can affect mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and 4 levels. Importantly, the changes observed in SIRT6 deficient brains are observed in brains of aging people, but the overlapping is greater in patients with Alzheimers, Parkinsons, Huntingtons, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that reduced levels of SIRT6 in the aging brain and neurodegeneration could initiate mitochondrial dysfunction by altering gene expression, ROS production and mitochondrial decay.

cell biology↗

bioRxiv2020

Molecular Mechanism of Nuclear Tau Accumulation and its Role in Protein Synthesis.

Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Tau-K174Q expressing cells showed changes in the nucleolus increasing their intensity and number, as well as in rRNA synthesis leading to an increase in protein translation and ATP reduction. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.

molecular biology↗

bioRxiv2019

SIRT6 is a DNA double-strand break sensor

DNA double strand breaks are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure, with high affinity for double strand breaks. It relocates to sites of damage independently of signalling and known sensors and activates downstream signalling cascades for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of the Homologous Recombination and Non-Homologous End Joining pathways. Our findings indicate that SIRT6 plays a previously uncharacterized role as DNA damage sensor, which is critical for initiating the DNA damage response (DDR). Moreover, other Sirtuins share some DSB binding capacity and DDR activation. SIRT6 activates the DDR, before the repair pathway is chosen, and prevents genomic instability. Our findings place SIRT6 at the top of the DDR and pave the road to dissect the contributions of distinct double strand break sensors in downstream signalling.

biochemistry↗