Biology subjects

Meyer, D. H.

Publications and source records attributed to Meyer, D. H..

6 recordsLinked to original sources

bioRxiv2025

The DREAM complex links somatic mutation, lifespan, and disease

The DREAM complex has emerged as a central repressor of DNA repair, raising questions as to whether such repression exerts long-term effects on human health. Here we establish that DREAM activity significantly impacts lifetime somatic mutation burden, and that such effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM activity and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM activity have decreased mutation rates. Second, DREAM activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM activity in Alzheimers patients predicts late disease onset and decreased risk for severe neuropathology. Finally, we show DREAM knockout protects against mutation accumulation in vivo, reducing single-base substitutions by 4.2% and insertion/deletions by 19.6% in brains of mice. These findings position DREAM as a key regulator of aging.

bioinformatics↗

bioRxiv2025

Age deceleration and reversal gene patterns in dauer diapause

The aging process is characterized by a general decrease in physical functionality and poses the biggest risk factor for a variety of diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders among others. Understanding the naturally evolved mechanisms that slow aging and rejuvenate an animal could reveal important concepts how to prevent age-associated diseases and even revert aging. The C. elegans dauer state is a robust and long-lived alternative developmental state that after dauer exit has a normal adult lifespan with fully retained fecundity. To understand how longevity during dauer and rejuvenation following dauer exit is mediated, we characterized the gene expression changes during dauer and upon exit. We assessed how biological age, as determined via BiT Age, a transcriptome aging clock, is affected during dauer and upon dauer exit. During the dauer stage, we measured a decelerated increase in age compared to the chronological age and an age reversal following dauer exit. Transcriptomic analyses revealed major metabolic shifts and enhanced biomolecular degradation that are reversed during exit. Moreover, we show that transcription-blocking lesions can induce lasting transcription stress in dauers that is rapidly resolved by transcription-coupled nucleotide excision repair during dauer exit. Our data provide new insights into the underlying mechanisms of naturally occurring age deceleration and rejuvenation.

systems biology↗

bioRxiv2025

Resilience and restoration from fasting-refeeding mediated by a nutrient-regulated linker histone

Intermittent fasting and fasting-refeeding regimens can slow biological aging across taxa1. Shifts between fed and fasted states activate ancient nutrient-sensing pathways which alter cellular and epigenetic states to promote longevity2-4. Yet how biological age trajectories progress during fasting-refeeding, and how nutrient-sensing pathways reprogram epigenetic state remain largely unknown. Here we observe increases in predicted biological age of Caenorhabditis elegans during prolonged fasting in adult reproductive diapause, followed by extraordinary reduction of biological age during refeeding. We identify hil-1/H1-0 as an evolutionarily conserved nutrient-regulated linker histone which mediates adaptations to fasting and refeeding downstream of FOXO and TFEB transcription factors. In C. elegans and human cell culture, hil-1/H1-0 upregulation during low-nutrient states promotes long-term survival and subsequent refeeding-induced recovery. Restoration of C. elegans after prolonged fasting is improved by enhancing the natural downregulation of hil-1 specifically during refeeding. Our study identifies HIL-1/H1.0 as part of an ancestral epigenetic switch during fasting-refeeding that reprograms metabolic and cellular states underlying resilience and restoration.

genetics↗

bioRxiv2024

Thermosensory neurons control genetic inheritance through regulation of germline transposons

Transposable elements (TEs) can alter genome structure through transposition, and their activity is therefore tightly restricted by small RNA-mediated and chromatin-based silencing mechanisms. In C. elegans, elevated temperature can induce TE expression, raising the question of whether thermosensory neurons influence TE regulation. Here, we investigated the role of the AFD thermosensory neurons in TE regulation using multiple models of AFD dysfunction that altered TE expression; Mirage transposase induction emerged as the most reproducible phenotype across all AFD-dysfunctional strains. In the AFD triple mutant strain (PY9248), we observed strong Tc1 transposase expression, and genome-wide Tc1-enriched de novo insertions over generations. However, CRISPR reconstruction of the genotype in the N2 background did not reproduce the strong Tc1 phenotype, indicating that Tc1 activation and mutagenesis in PY9248 are background-associated rather than solely caused by loss of gcy-8, gcy-18, gcy-23 function. These findings support a model in which AFD neuron dysfunction reproducibly alters TE expression, particularly of Mirage, while heritable Tc1-mediated mutagenesis requires an additional, currently uncharacterized factor present in the AFD triple mutant background.

genetics↗

bioRxiv2024

Perception of Temperature Even in the Absence of Actual Change is Sufficient to Drive Transgenerational Epigenetic Inheritance

Can processes occurring in one individuals nervous system influence the physiology of the descendants? Here, we explored the hypothesis that parents sensation or perception of environmental cues can influence their offspring, extending across many subsequent generations. We show that in Caenorhabditis elegans, temperature perception by the AFD thermosensory neurons initiates a signaling cascade that, directly or indirectly, induces transgenerational changes in RNAi factors, small RNAs, and their target genes. Moreover, we identify secreted factors that enable this neuron-to-germline communication and trace the path of the epigenetic signal. We further model the process mathematically, and the model yields new predictions that we validate experimentally: blocking sensory input dampens RNAi inheritance initiated by exogenous double-stranded RNA (dsRNA). Together, our results demonstrate that sensory perception is sufficient to influence small RNA-mediated heritable gene expression memory.

genetics↗

bioRxiv2022

Sensory neurons safeguard from mutational inheritance by controlling the CEP-1/p53-mediated DNA damage response in primordial germ cells

The genome integrity control in primordial germ cells (PGCs) is prerequisite for the inheritance of stable genomes. The PGCs in C. elegans are embedded in a somatic niche that regulates its DNA damage response (DDR). Here, we show that the AMPK-like kinases KIN-29 and AAK-2 are required for arresting PGCs carrying persistent DNA damage. We determined that the ASI neurons, which sense environmental conditions such as nutrient availability, secrete the TGF-beta-like ligand DAF-7 that is recognized by the DAF-1 receptor in PGCs. ASI-dependent DAF-7 signaling regulates the induction of CEP-1/p53 in the PGCs amid persistent DNA damage. Using single worm whole genome sequencing, we establish that defective ASI control of the CEP-1/p53-regulated DDR in PGCs ultimately results in the inheritance of de novo germline mutations. Our results indicate that sensory neurons safeguard from the inheritance of germline mutations suggesting the possibility that perception of the environment could direct genetic inheritance. One sentence summaryThe ASI sensory neurons regulate the CEP-1/p53-dependent DNA damage response of primordial germ cells via TGF-beta signaling and influence inherited mutational burden.

genetics↗