Biology subjects

Schumacher, B.

Publications and source records attributed to Schumacher, B..

15 recordsLinked to original sources

bioRxiv2026

A molecular circuit integrates environmental cues to coordinate the exit from developmental dormancy

Diapause is a reversible dormancy state that enables organisms to survive extreme environments. In annual killifishes, embryos use diapause to bridge seasonal drought, but how environmental cues are integrated to trigger exit remains unclear. Here, we combine model-based single-embryo transcriptomics with cross-clade small-molecule screening to define the molecular logic of diapause exit. In the African turquoise killifish (Nothobranchius furzeri), high-resolution profiling uncovered a temporal transcriptional cascade, while transcriptomic-clock analysis revealed reduced transcriptional noise during developmental reactivation. Transcriptome-guided drug-enrichment analysis nominated overlapping compounds across two annual killifish clades, leading to a targeted chemical screen that identified shared activators and inhibitors of diapause exit. Functional assays support a model in which HSP90 integrates temperature-dependent cues with steroid-hormone signaling. Together, these findings reveal shared molecular machinery that couples environmental sensing to developmental timing, aligns diapause exit with favorable conditions, and provides a powerful comparative framework for dissecting vertebrate dormancy control.

developmental biology↗

bioRxiv2026

Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging

Elevated sulfur-containing amino acids (SAA; methionine and cystine) are linked to human mortality. While methionine restriction (MR) extends lifespan in animals, it is often ignored that traditional longevity-promoting MR diets also lack cystine. When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via cystathionine {gamma}-lyase (CTH) in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged Cth-/- mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.

physiology↗

bioRxiv2026

Neuronal DNA repair mediates systemic mitochondrial maintenance through acetylcholine signaling

DNA repair defects such as Nucleotide Excision Repair (NER) mutations can lead to progeroid syndromes characterized by growth retardation and accelerated aging with distinct tissue type specific pathologies. DNA damage induced dysfunction of specific cell types can impair the organisms overall function. It is unknown whether, in reverse, DNA repair in specific tissues can have non-cell-autonomous consequences on other tissues carrying DNA damage. To explore the organismal consequences of cell type specific DNA repair, we restricted NER activity to specific tissues and monitored consequences on organismal health in C. elegans. Unexpectedly, we observed that tissue specific DNA repair is sufficient to improve overall DNA damage resistance. Strikingly, the sole NER activity in neurons is sufficient to provide similar overall DNA damage resistance as whole body NER. We show that this systemic DNA damage resilience is mediated by neuronal Acetylcholine signaling that promotes the maintenance of mitochondrial activity throughout the organism.

genetics↗

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↗

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↗

bioRxiv2020

The auxin transporter PIN1 and the cytokinin transporter AZG1 interact to regulate the root stress response

Root system development is crucial for optimal growth and yield in plants, especially in sub-optimal soil conditions. The architecture of a root system is environmentally responsive, enabling the plant to exploit regions of high nutrient density whilst simultaneously minimizing abiotic stress. Despite the vital contribution of root systems to the growth of both model and crop species, we know little of the mechanisms which regulate their architecture. One factor which is relatively well understood is the transport of auxin, a plant growth regulator which defines the frequency of lateral root (LR) initiation and the rate of LR outgrowth. Here we describe a search for proteins which regulate RSA by interacting directly with a key auxin transporter, PIN1. The native separation of PIN1 identified several co-purifying proteins. Among them, AZG1 was subsequently confirmed as a PIN1 interactor. AZG1-GFP fusions co-localized with PIN1 in procambium cells of the root meristem. Roots of azg1 plants contained less PIN1 and blocking proteolysis restored PIN1 levels, observations which are consistent with PIN1 being stabilized by AZG1 in the plasma membrane. Furthermore, we show that AZG1 is a cytokinin import protein; accordingly, azg1 plants are insensitive to exogenously applied cytokinin. In wild-type plants, the frequency of LRs falls with increasing salt concentration, a response which is not observed in azg1 x azg2 plants, although their drought response is unimpaired. This report therefore identifies a potential point for auxin:cytokinin crosstalk in the environmentally-responsive determination of root system architecture.

plant biology↗

bioRxiv2020

DNA damage activates mTORC1 signaling in podocytes leading to glomerulosclerosis

DNA repair is essential for preserving genome integrity and ensuring cellular functionality and survival. Podocytes, post-mitotic glomerular epithelial cells, bear limited regenerative capacity, and their survival is indispensable to maintain the function of the kidneys filtration units. While podocyte depletion is a hallmark of the aging process and of many proteinuric kidney diseases, the underlying factors remain unclear. We investigated DNA repair in podocyte diseases by using a constitutive and an inducible podocyte-specific knockout mouse model for Ercc1, a multifunctional endonuclease cofactor involved in nucleotide excision repair (NER), interstrand crosslink (ICL) repair, and DNA double-strand break (DSB) repair. We assessed the consequences of Ercc1 loss in vivo, complemented by mechanistical in vitro studies of induced DNA damage in cultured podocytes. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages as well as in patient biopsies with minimal change disease and focal segmental glomerulosclerosis. Podocyte-specific Ercc1 knockout resulted in accumulation of DNA damage with ensuing proteinuria, podocyte loss, glomerulosclerosis, renal insufficiency, and reduced lifespan. The response to genomic stress was different to the pattern reported in other cell types, as podocytes activated mTORC1 signaling upon DNA damage in vitro and in vivo. The induced mTORC1 activation was abrogated by inhibiting DNA damage response through DNA-PK and ATM kinases in vitro. Moreover, pharmacological inhibition of mTORC1 modulated the development of glomerulosclerosis in Ercc1-deficient mice. Perturbed DNA repair gene expression and genomic stress was also detected in podocytes of human focal segmental glomerulosclerosis, characterized by podocyte loss. Beyond that, DNA damage accumulation occurred in podocytes of healthy aging mice and humans. These findings reveal that genome maintenance is crucial for podocyte maintenance, linked to the mTORC1 pathway, and involved in the aging process as well as in the development of glomerulosclerosis, potentially serving as a therapeutic target in the future.

cell biology↗

bioRxiv2020

A transcriptome based aging clock near the theoretical limit of accuracy

Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this transcriptome clock can also be applied to human age prediction with high accuracy. This transcriptome aging clock could therefore find wide application in genetic, environmental and therapeutic interventions in the aging process.

bioinformatics↗

bioRxiv2020

Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

cell biology↗

bioRxiv2020

ATM-mediated DNA damage response in macrophages primes phagocytosis and immune checkpoint regulation

Genotoxin-based cancer therapies trigger a DNA damage response (DDR) to eliminate cancer cells but similarly exert profound alterations to the immune cell compartment. Macrophages in the tumor microenvironment are important and multifaceted components in actively sustaining tumor progression but also in clearance of tumor cells and play an important role in the outcome of chemotherapy. Here, we report that post neo-adjuvant chemotherapy macrophages in tumor samples display elevated expression of the immune checkpoint PD-L1. We determined that chemotherapy or direct application of DNA damage to macrophages in vitro triggers a specific MDDR polarization phenotype characterized by increased phagocytic activity, elevated PD-L1 expression, and induction of endotoxin tolerance. Phospho-proteomics analysis revealed epigenetic alterations and ATM-dependent induction of senescence in macrophages upon DNA damage. We propose that ATM-induced senescence and PD-L1 immune checkpoint induction mediate a specific MDDR macrophage polarization that might contribute to chemotherapy responses. Furthermore, our results clarify the functional role of tumor associated macrophages in the context of DNA damage and combination therapies including checkpoint inhibition.

immunology↗

bioRxiv2020

Arabidopsis AZG2, an auxin induced putative cytokinin transporter, regulates lateral root emergence

The phytohormones cytokinin (CK) and auxin are key regulators of plant growth and development. During the last decade specialised transport mechanisms turned out to be the key for the control of local and long distance hormone distributions. In contrast to auxin, CK transport is poorly understood. Here we show that Arabidopsis thaliana AZG2, a member of the AZG purine transporter family, acts as CK transporter involved in the determination of the root system architecture. The expression of AtAZG2 is primarily auxin dependent and restricted to a small group of cells surrounding the lateral root primordia. Compared to wild type, mutants carrying loss-of-function alleles of Atazg2 have higher density of lateral roots, suggesting AZG2 as being part of a regulatory pathway in lateral root emergence. Moreover, azg2 mutants are partially insensitive to exogenously applied CK, which is consistent with the observation that the CK reporter gene TCSnpro:GFP showed lower fluorescence signal in the roots of azg2 mutants compared to those of wild type. These results indicate a defective CK signalling pathway in the region of lateral root primordia. By the integration of AtAZG2 subcellular localization and CK transport capacity data, our results allowed us to propose a local Auxin/CK signalling model for the regulation of lateral root emergence.

plant biology↗

bioRxiv2018

Activation of the endoplasmic reticulum unfolded protein response reverses an inflammation-like response to cytoplasmic DNA

Innate immune responses protect organisms against various insults, but may lead to tissue damage when aberrantly activated. In higher organisms, cytoplasmic DNA can trigger inflammation that can lead to tissue degeneration. Simpler in vivo models could shed new mechanistic light on how inflammatory responses to cytoplasmic DNA lead to pathology. Here we show that in DNase II-deficient Caenorhabditis elegans, persistent foreign cytoplasmic DNA leads to systemic tissue degeneration, and we identify impaired protein homeostasis as an inflammatory pathomechanism. This pathological outcome can be alleviated by improving protein homeostasis, either via ectopic induction of the endoplasmic reticulum unfolded protein response (UPRER) or by treatment with N-acetylglucosamine. Our results establish C. elegans as an ancestral metazoan model for studying outcomes of inflammation-like conditions caused by persistent cytoplasmic DNA and provide insight into potential therapies for conditions involving chronic inflammation.

cell biology↗