Biology subjects

Statzer, C.

Publications and source records attributed to Statzer, C..

11 recordsLinked to original sources

bioRxiv2024

A VHL-1/HIF-1/SQRD1/COL-88 axis links extracellular matrix formation with longevity in Caenorhabditis elegans

The extracellular matrix (ECM) is a pivotal three-dimensional network crucial for tissue organization, cellular communication, and fundamental cellular processes, where collagens are the major chemical entity in amount. ECM deregulation is directly involved with several pathologies, such as tumour growth and invasiveness, atherosclerosis, and diabetic nephropathy. Mutations in the von Hippel-Lindau tumour suppressor (pVHL) cause VHL syndrome, a multi-tumour syndrome commonly associated with clear cell renal carcinoma (ccRCC). Loss of pVHL is associated with the activation of hypoxia-inducible factor (HIF) signaling. Mutation of VHL-1 in the nematode Canorhabditis elegans has been shown to increase lifespan and stress resistance. Interestingly, considering recent findings on the involvement of collagens in the regulation of lifespan, we also observed these animals to show defects in body morphology in a HIF-1 dependent manner. Based on this finding, we established a link between HIF-1 activation upon loss of VHL-1 and ECM defects associated with alterations in collagen expression. An RNAi screen examining genes upregulated in vhl-1 mutant worms revealed the sulfide quinone oxidoreductase sqrd-1 to mediate the change in body morphology. SQRD-1 is essential to the HIF-1 dependent increase in several collagen genes. One of these genes, col-88, partly mediates both the impact of loss of VHL-1 on lifespan extension and body length. The downregulation of the uncharacterised col-88 partially restores lifespan extension and reduces body size of vhl-1/sqrd-1 to vhl-1(ok161) single mutant. This study contributes to the increasing body of evidence linking lifespan extension and the ECM and now implicates this axis in hypoxia-signaling. These findings are of special interest considering the role of ECM integrity in tumour growth and metastasis. Author SummaryThe extracellular matrix and its composing collagens are associated with a wide number of diseases, including cancer. The von Hippel-Lindau tumour suppressor (pVHL) is known to work by regulating the Hypoxia Inducible Factor (HIF) to help the organism to adapt to lack of oxygen. Mutations in pVHL are associated with clear cell renal carcinoma (ccRCC). Interestingly, a small number of studies have shown that pVHL can be directly associated with collagens, a function that is independent of its classical role regulating HIF. However, there is no further knowledge about which role the hypoxia pathway has when it comes to extracellular matrix formation and function, what would be useful since the invasiveness of cancers, such as ccRCC, are directly connected to their matrix/collagen composition. Here we observed that the model organism C. elegans has drastically different collagen composition and body size upon a mutation on its vhl-1 gene. Furthermore, a protein previously only known to be involved in sulfide metabolism, SQRD-1, connects body size and lifespan in this animal model, revealing a surprising link between the hypoxia pathway and sulfur metabolism to control lifespan. Further studies could target sulfur metabolism in ccRCC to modulate collagen production and tumour invasiveness.

genetics↗

bioRxiv2022

Patient-derived tumoroids of advanced high-grade neuroendocrine neoplasms mimic patient chemotherapy responses and guide the design of personalized combination therapies

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous epithelial malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses. PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.

cancer biology↗

bioRxiv2022

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity in C. elegans

Although it is postulated that dysfunctional extracellular matrices (ECM) drive aging and disease, how ECM integrity assures longevity is unknown. Here, using proteomics and in-vivo monitoring of fluorescently tagged ECM proteins, we systematically examined the ECM composition during Caenorhabditis elegans aging revealing three distinct collagen dynamics. We show that age-dependent stiffening of inert collagen was slowed by longevity interventions through prolonged replenishing of collagens. In genetic and automated lifespan screens for the regulators that drive this remodeling, we identify hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression across tissues. The hemidesmosome tension-induced adaptation is mediated via transcriptional co-activator YAP. Our data reveal a novel mechanism of mechano-coupling and synchronizing of two functionally distinct and spatially distant ECMs that is indispensable for longevity. Thus, besides signaling molecules, mechanotransduction-coordinated ECM remodeling systemically promotes healthy aging. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/505802v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1b45b6dorg.highwire.dtl.DTLVardef@1de8e80org.highwire.dtl.DTLVardef@5da7b2org.highwire.dtl.DTLVardef@acc577_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIProteomics, genetics screen, and automated lifespan assays of >55000 animals all point to hemidesmosome-containing structures for the mechano-regulation of ECM homeostasis and longevity C_LIO_LICoupling of biomechanical properties of two ECMs with underlying cellular signaling C_LIO_LITranscriptional co-activator YAP-1 is required for longevity and pressure-induced collagen homeostasis C_LI

molecular biology↗

bioRxiv2022

Condensin I folds the C. elegans genome

The Structural Maintenance of Chromosomes (SMC) complexes, cohesin and condensins, are named for their roles in separating and compacting chromosomes during meiosis and mitosis. Recent data from mammalian cells have revealed additional functions for cohesin, including folding the interphase genome into loops and domains. However, it remains unclear what determines genome folding in holocentric species. To address this question, we systematically and acutely inactivated each SMC complex. Surprisingly, we found that, in contrast to mammals, condensin I is the major long-range genome loop extruder, while cohesin only creates small loops. Specifically, loss of condensin I led to genome-wide decompaction, chromosome mixing, and the disappearance of topologically associating domain (TAD) structures, while reinforcing fine-scale epigenomic compartments. Strikingly, inactivating condensin I and its X-specific variant condensin IDC from the X chromosomes revealed the existence of a third compartment that groups together a subset of previously characterized loading sites for condensin IDC and binding sites for the X-targeting complex SDC. Although the inactivation of cohesin, condensin II, and condensin I/IDC led to minor transcriptional changes for all autosomes, removing condensin I/IDC from the X chromosome resulted in the up-regulation of X-linked genes. In conclusion, our findings describe a novel function for C. elegans condensin I/IDC in organizing holocentric interphase chromosomes, which substitutes for the role played by cohesin in mammals.

molecular biology↗

bioRxiv2021

Rilmenidine mimics caloric restriction via the nischarin I1-imidazoline receptor to extend lifespan in C. elegans

Caloric restriction increases lifespan across species and has health benefits in humans. Because complying with a low-calorie diet is challenging, here we investigated pharmacological interventions mimicking the benefits of caloric restriction. Searching for compounds that elicit a similar gene expression signature to caloric restriction, we identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating C. elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, healthspan, and lifespan benefits upon rilmenidine treatment in worms are mediated by the I1-imidazoline receptor nish-1, implicating this receptor as a potential longevity target. Furthermore, we show that rilmenidine treatment increased ERK phosphorylation via NISH-1. Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to caloric restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine-induced longevity required the transcription factors FOXO/DAF-16 and NRF1,2,3/SKN-1, both important for caloric restriction-mediated longevity. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity. Lastly, we find that treating mice with rilmenidine showed transcriptional changes in liver and kidney similar to caloric restriction. Overall, our findings reveal rilmenidine as a caloric restriction mimetic and as a novel geroprotective compound.

pharmacology and toxicology↗

bioRxiv2021

Longevity interventions temporally scale healthspan in Caenorhabditis elegans

Human centenarians and longevity mutants of model organisms show lower incidence rates of late-life morbidities than the average population. However, whether longevity is caused by a compression of the portion of life spent in a state of morbidity, i.e., "sickspan," is highly debated even in isogenic C. elegans. Here, we developed a microfluidic device that employs acoustophoretic force fields to quantify the maximum muscle strength and dynamic power in aging C. elegans. Together with different biomarkers for healthspan, we found a stochastic onset of morbidity, starting with a decline in dynamic muscle power and structural integrity, culminating in frailty. Surprisingly, we did not observe a compression of sickspan in longevity mutants but instead observed a temporal scaling of healthspan. Given the conservation of these longevity interventions, this raises the question of whether the healthspan of mammalian longevity interventions is also temporally scaled.

systems biology↗

bioRxiv2021

Youthful and age-related matreotypes predict drugs promoting longevity

The identification and validation of drugs that promote health during aging ( geroprotectors) is key to the retardation or prevention of chronic age-related diseases. Here we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this novel observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a youthful matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for C. elegans longevity. With this reporter, we were able to eliminate false positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging. HighlightsO_LIMany geroprotective drugs alter extracellular matrix gene expression C_LIO_LIDefined young and old human matreotype signatures can identify novel potential geroprotective compounds C_LIO_LIProlonged collagen homeostasis as a surrogate marker for longevity C_LI

pharmacology and toxicology↗

bioRxiv2020

ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1

Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

physiology↗

bioRxiv2020

The Molecular Landscape of the Aging Mouse Liver

Systems biology approaches often use inferred networks of gene expression and metabolite data to identify regulatory factors and pathways connected with phenotypic variance. Generally, study-specific multi-layer "Omics" datasets are used to contextualize generic molecular networks. In this regard separating upstream causal mechanisms, downstream biomarkers, and incidental correlations remains a significant challenge, yet it is essential for designing mechanistic experiments. To address this, we designed a study following a population of 2157 individuals from 89 isogenic BXD mouse strains across their lifespan to identify molecular interactions among genotype, environment, age (GxExA) and metabolic fitness. Each strain was separated into two cohorts, one fed low fat (6% cal/fat) and the other high fat (60% cal/fat) diets. Tissues were collected for 662 individuals (309 cohorts) diverging across age (7, 12, 18, and 24 months), diet, sex, and strain. Transcriptome, proteome, and metabolome data were generated for liver. Of these we identified linear relations among these molecular data with lifespan for the same genomes of mice (Roy et al. 2020), and we defined [~]1100 novel protein-coding genes associated with longevity. We knocked down the ortholog of Ctsd in C. elegans. The treatment reduced longevity both in wildtype and in mutant long-lived strains, thus validating the prediction. Next, to assess the molecular impact of GxExA on gene expression, the multi-omics data was parsed into metabolic networks where connectivity varied due to the independent variables. Differences in edge strengths connecting nodes in these molecular networks according to each variable enabled causal inference by using stability selection, with roughly 21% of novel gene-pathway connections being causally affected by diet and/or age. For instance, Chchd2 is activated by aging and drives changes in the proteasome, oxidative phosphorylation, and mitochondrial translation transcriptional networks. Together, we have developed a large multi-omics resource for studying aging in the liver, and a resource for turning standard associations into causal networks.

systems biology↗

bioRxiv2020

The extracellular matrix phenome across species

Extracellular matrices are essential for cellular and organismal function. Recent genome-wide and phenome-wide association studies started to reveal a broad spectrum of phenotypes associated with genetic variants. However, the phenome or spectrum of all phenotypes associated with genetic variants in extracellular matrix genes is unknown. Here, we analyzed over two million recorded genotype-to-phenotype relationships across hundreds of species to define their extracellular matrix phenomes. By using previously defined matrisomes of humans, mice, zebrafish, Drosophila, and C. elegans, we found that the extracellular matrix phenome comprises of 3-10% of the entire phenome. Collagens (COL1A1, COL2A1) and fibrillin (FBN1) are each associated with more than 150 distinct phenotypes in humans, whereas collagen COL4A1, Wnt- and sonic hedgehog (shh) signaling are predominantly associated in other species. We determined the phenotypic fingerprints of matrisome genes and found that MSTN, CTSD, LAMB2, HSPG2, and COL11A2 and their corresponding orthologues have the most phenotypes across species. Out of the 42558 unique matrisome genotype-to-phenotype relationships across the five species with defined matrisomes, we have constructed interaction networks to identify the underlying molecular components connecting with orthologues phenotypes and with novel phenotypes. Thus, our networks provide a framework to predict unassessed phenotypes and their potential underlying molecular interactions. These frameworks inform on matrisome genotype-to-phenotype relationships and potentially provide a sophisticated choice of biological model system to study human phenotypes and diseases. HighlightsO_LI7.6% of the human phenome originates from variations in matrisome genes C_LIO_LI11671 phenotypes are linked to matrisome genes of humans, mice, zebrafish, Drosophila, and C. elegans C_LIO_LIExpected top ECM phenotypes are developmental, morphological and structural phenotypes C_LIO_LINonobvious top ECM phenotypes include immune system, stress resilience, and age-related phenotypes C_LI

systems biology↗

bioRxiv2019

Heterogeneity in heat shock response dynamics caused by translation fidelity decline and proteostasis collapse

Genetics, environment, and stochasticity influence the rate of ageing in living organisms. Individual Caenorhabditis elegans that are genetically identical and cultured in the same environment have different lifespans, suggesting a significant role of stochasticity in ageing. We have developed a novel microfluidic methodology to measure heat-shock response as a surrogate marker for heterogeneity associated with lifespan and have quantified the heat-shock response of C. elegans at the population, single individual, and tissue levels. We have further mathematically modelled our data to identify the major drivers determining such heterogeneity. This approach demonstrates that protein translation and degradation rate constants explain the individuality of the heat-shock time-course dynamic. We observed a decline of protein turnover capacity in early adulthood, co-incidentally occurring as the predicted proteostasis collapse. We identified a decline of intestinal response as the tissue that underlies the individual heterogeneity. Additionally, we verified that individuals with enhanced translation fidelity in early adulthood live longer. Altogether, our results reveal that the stochastic onset of proteostasis collapse of somatic tissues during early adulthood reflects individual protein translation capacity underlying heterogenic ageing of isogenic C. elegans.

bioengineering↗