Biology subjects

Groth, M.

Publications and source records attributed to Groth, M..

At least 19 recordsLinked to original sources

bioRxiv2025

The chloride cotransporter NKCC1 regulates self-renewal of hippocampal neural stem cells via the transcription factor Sox11

The GABAergic-mediated depolarization plays a key role in controlling stem cell fate and neurogenesis within the dentate gyrus of the hippocampal formation. This depolarization effect is highly dependent on the balance between the chloride co-transporters NKCC1 and KCC2. It is not known how changes in NKCC1 modulate the fate of Nestin-positive stem cells (NSCs) in the hippocampus during adult neurogenesis. In our study, we demonstrate that a knockout of Nkcc1 in NSCs increase their proliferation by symmetric self-renewal and expand the stem cell pool. Using single-cell RNA sequencing, we identified Sox11 as a key transcription factor that is significantly downregulated following Nkcc1 knockout. In agreement with this finding, we found that Sox11 knockout enhances proliferation and self-renewal of NSCs, which is also marked by an increase in symmetric stem cell division. Based on these findings, we propose that altering Nkcc1 expression in NSCs shifts their fate from neurogenesis towards self-renewal via Sox11 regulation. Furthermore, we observed that NKCC1 levels decline in NSCs during aging, which correlates with a further increase in self-renewal. Our data strongly suggest that the age-related decline in NKCC1 levels promote symmetric division and self-renewal contributing to the age-dependent decrease in neurogenesis. NKCC1 via Sox11 is a key regulator of NSCs fate decision, critically balancing self-renewal and neuronal differentiation in the adult hippocampus. HighlightsNKCC1 is a key factor in regulating the Nestin-positive neural stem cell symmetric self-renewal. Sox11 is a downstream effector of NKCC1 in Nestin-positive stem cells and is involved in expansion of the stem cell pool. Aging reduces NKCC1 expression in Nestin-positive stem cells and increases their self-renewal. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/662334v1_ufig1.gif" ALT="Figure 1000"> View larger version (38K): org.highwire.dtl.DTLVardef@1babdcforg.highwire.dtl.DTLVardef@1038bfborg.highwire.dtl.DTLVardef@1db105corg.highwire.dtl.DTLVardef@10f2cde_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

The Aging Synapse: An Integrated Proteomic And Transcriptomic Analysis

An important hallmark of aging is the loss of proteostasis, which can lead to the formation of protein aggregates and mitochondrial dysfunction in neurons. Although it is well known that protein synthesis is finely regulated in the brain, especially at synapses, where mRNAs are locally translated in activity-dependent manner, little is known as to the changes in the synaptic proteome and transcriptome during aging. Therefore, this work aims to elucidate the relationship between transcriptome and proteome at soma and synaptic level during aging. Proteomic and transcriptomic data analysis reveal that, in young animals, proteins and transcripts are correlated and synaptic regulation is driven by changes in the soma. During aging, there is a decoupling between transcripts and proteins and between somatic and synaptic compartments. Furthermore, soma-synapse gradient of ribosomal genes changes upon aging, i.e. ribosomal transcripts are less abundant and ribosomal proteins are more abundant in synaptic compartment of old mice with respect to younglings. Additionally, transcriptomics data highlight a difference in the splicing of certain synaptic mRNA with aging. Taken together, our data provide a valuable resource for the study of the aging synapse.

neuroscience↗

bioRxiv2024

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

Aberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by TBXT is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. Here, we developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT, inhibiting its binding to DNA and expression. In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced morphologic changes indicative of senescence and differentiation. Combining T-DARPin-mediated TBXT inhibition with transcriptomic and proteomic analyses, we determined the TBXT regulome in chordoma cells, which comprises in particular networks involved in cell cycle regulation, DNA replication and repair, embryonal cell identity, metabolic processes, and interferon response. The analysis of selected TBXT regulome components provided new insights into chordoma biology, such as the strong upregulation of IGFBP3 upon TBXT inhibition to fine-tune part of TBXTs downstream effectors. Finally, we assigned each TBXT regulome member a druggability status to create a resource for future translational studies and found high interferon response signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with strong sensitivity to clinically approved JAK2 inhibitors. These findings demonstrate the potential of DARPins to investigate the function of nuclear proteins to understand the regulatory networks of cancers driven by aberrant transcription factor activity, including novel entry points for targeted therapies that warrant testing in patients.

cancer biology↗

bioRxiv2024

The Greenland shark (Somniosus microcephalus) genome provides insights into extremelongevity

The Greenland shark (Somniosus microcephalus) is the longest-lived vertebrate known, with an estimated lifespan of [~] 400 years. Here, we present a chromosome-level assembly of the 6.45 Gb Greenland shark, rendering it one of the largest non-tetrapod genomes sequenced so far. Expansion of the genome is mostly accounted for by a substantial expansion of transposable elements. Using public shark genomes as a comparison, we found that genes specifically duplicated in the Greenland shark form a functionally connected network enriched for DNA repair function. Furthermore, we identified a unique insertion in the conserved C-terminal region of the key tumor suppressor p53. We also provide a public browser to explore its genome.

genomics↗

bioRxiv2024

Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

Aging is the predominant cause of morbidity and mortality in industrialized countries. The specific molecular mechanisms that drive aging are poorly understood, especially the contribution of the microbiota in these processes. Here, we combined multi-omics with metabolic modeling in mice to comprehensively characterize host-microbiome interactions and how they are affected by aging. Our findings reveal a complex dependency of host metabolism on microbial functions, including previously known as well as novel interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome, which we attribute to reduced beneficial interactions in the microbial community and a reduction in its metabolic output. These microbial changes coincided with a corresponding downregulation of key host pathways predicted by our model to be dependent on the microbiome that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. These pathways could serve as future targets for the development of microbiome-based therapies against aging. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/587009v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@a8e7faorg.highwire.dtl.DTLVardef@115f35aorg.highwire.dtl.DTLVardef@1bbf32org.highwire.dtl.DTLVardef@1a58c7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2023

Transcriptome analysis of different strains of the turquoise killifish Nothobranchius furzeri identifies signatures associated with heritable lifespan differences

The killifish Nothobranchius furzeri is the shortest-lived vertebrate model organism and is characterized by laboratory strains differing in lifespan by more than a factor of two. The genetic architecture underlying this difference is complex and the pathways responsive remain elusive. We performed an analysis in N. furzeri of public transcritomic datasets comprehensive of four different tissues and one embryonic stage in two strains: the shorter-lived GRZ and the longer-lived MZM0410. Remarkably, the two strains differ in their transcriptome profile already at the embryonic stage. The short-lived strain GRZ shows an anticipated aging profile consistently in all tissues investigated, with differences in expression of aging-related genes detected already at sexual maturity. In addition, analysis of a longitudinal dataset revealed that genes whose expression is prognostic of longer lifespan at the individual level are also differentially expressed between strains at an early adult age, suggesting antagonistic pleiotropism.

genomics↗

bioRxiv2023

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer's disease

Recent research revealed that Tau plays critical roles in various neuronal functions. Our previous work demonstrated that destabilization and nuclear delocalization of Tau can alter the expression of glutamatergic genes, thereby mediating early neuronal damage. Upon analysing gene coexpression of AD temporal regions at different stages and the transcriptional output in differentiated neuroblastoma cells, we discovered that changes in Tau availability are linked to global alterations in gene expression that affect multiple neuronal pathways. Comparison with the human AD temporal region showed that the Tau-dependent modulation of gene expression closely resembles an intermediate stage of AD that precedes the definitive AD condition. Furthermore, we identified the chromatin remodelling pathway as being significantly affected by Tau in both our cellular model and AD brains, with reductions in heterochromatin markers. We propose that Tau is able to globally affect the neuronal transcriptome and that its availability is linked to changes in gene expression during intermediate stages of AD development. In addition, we found that the epigenetic pathway is strongly affected by Tau during the progression of AD.

neuroscience↗

bioRxiv2023

The Tgf-β family member Gdf6Y determines the male sex in Nothobranchius furzeri by suppressing oogenesis-inducing genes

The short-lived African killifish Nothobranchius furzeri lives in seasonal freshwater ponds and has evolved remarkable traits to survive in this limited environment. One of those traits is a genetic XX/XY sex-determination system, which ensures an equal distribution of both sexes. Comparisons of female and male genomic sequences identified the Y-chromosomal copy of the TGF-{beta} family member gdf6 as the candidate male sex-determining (SD) gene, which was named gdf6Y in contrast to the X-chromosomal allele gdf6X. CRISPR/Cas9-mediated inactivation of gdf6Y in N. furzeri led to a complete male-to-female sex reversal in XY animals. The homozygous inactivation of gdf6X on the other hand led to a detrimental phenotype post-hatching. This phenotype was compensated by gdf6Y, revealing that the latter became the SD gene while retaining at least some of its original gdf6 function. Gdf6Y is expressed in testicular somatic cells already prior to hatching, where it represses the germ cell-intrinsic feminizing gene foxl2l. We have identified components of the TGF-{beta} signaling pathway, especially the inhibitor of DNA binding genes id1/2/3, and the mRNA decay activator zfp36l2, as Gdf6Y targets. We conclude that Gdf6Y exerts its function as the male sex-determining gene by suppressing female-specific genes in the developing gonad of male N. furzeri.

molecular biology↗

bioRxiv2022

Multi-omics analysis identifies RFX7 targets involved in tumor suppression and neuronal processes

Recurrently mutated in lymphoid neoplasms, the transcription factor RFX7 is emerging as a tumor suppressor. Previous reports suggested that RFX7 may also have a role in neurological and metabolic disorders. We recently reported that RFX7 responds to p53 signaling and cellular stress. Furthermore, we found RFX7 target genes to be dysregulated in numerous cancer types also beyond the hematological system. However, our understanding of RFX7s target gene network and its role in health and disease remains limited. Here, we generated RFX7 knock-out cells and employed a multi-omics approach integrating transcriptome, cistrome, and proteome data to obtain a more comprehensive picture of RFX7 targets. We identify novel target genes linked to RFXs tumor suppressor function and underscoring its potential role in neurological disorders. Importantly, our data reveal RFX7 as a mechanistic link that enables the activation of these genes in response to p53 signaling.

genomics↗

bioRxiv2022

A deep neural network provides an ultraprecise transcriptomic clock of the short-lived fish Nothobranchius furzeri and identifies predictive genes translatable to human aging.

A key and unresolved question in aging research is how to quantify aging at the individual level that led to development of "aging clocks", machine learning algorhythms trained to predict individual age from high-dimensional molecular data under the the assumption that individual deviations of the predicted age from the chronological age contain information on the individual condition (often referred to as "biological age"). A full validation of such clocks as biomarkers for clinical studies of ageing would require a comparison of their predictions with information on actual lifespan and long-term health. Such studies take decades in humans, but could be conducted in a much shorter time-frame in animal models. We developed a transcriptomic clock in the turquoise killifish Nothobranchius furzeri. This species is the shortest-lived vertebrate that can be cultured in captivity and is an emerging model organism for genetic and experimental studies on aging. We developed a proprietary deep learning architecture that autonomously selects a customizable number of input genes to use for its predictions in order to reduce overfitting and increase interpretability, and adopts an adversarial learning framework to identify tissue-independent transcriptional patterns. We called this architecture the Selective Adversarial Deep Neural Network (SA-DNN) and trained it on a multi-tissue transcriptomic dataset of N. furzeri. This SA-DNN predicted age of the test set with an accuracy of 1 day, i.e. less than 1% of the total species lifespan and detected genetic, pharmacological and environmental interventions that are known to influence lifespan in this species. Finally, a human transcriptomic multi-tissue clock that uses as input the orthologs of the genes selected by our SA-DNN in N. furzeri reaches an average error of[~] 3 years rivalling epigenetic clocks. Our SA-DNN represents the prototype of a new class of aging clocks that provide biomarkers applicable to intervention studies in model organisms and humans.

genomics↗

bioRxiv2022

RPG interacts with E3-ligase CERBERUS to mediate rhizobial infection in Lotus japonicus

Symbiotic interactions between rhizobia and legumes result in the formation of root nodules, which fix nitrogen that can be used for plant growth. Rhizobia usually invade legume roots through a plant-made tunnel-like structure called an infection thread (IT). Rhizobium-directed polar growth (RPG) encodes a coiled-coil protein that was identified in Medicago truncatula as required for root nodule infection, but the function of RPG remains poorly understood. In this study, we identified and characterized RPG in Lotus japonicus and determined that it is required for IT formation. RPG was induced by Mesorhizobium loti or purified Nodulation factor and displayed an infection-specific expression pattern. Nodule inception (NIN) bound to the RPG promoter and induced its expression. A GFP-RPG protein was localized in puncta subcellular localization in L. japonicus root protoplasts and in root hairs infected by M. loti. The N-terminal predicted C2 lipid-binding domain of RPG was not required for this subcellular localization or for function. CERBERUS, a U-box E3 ligase which is also required for rhizobial infection, was found to be localized in similar puncta. RPG co-localized and directly interacted with CERBERUS at the early endosomes (TGN/EE) compartment and near the nuclei in root hairs after rhizobia inoculation. Our study sheds light on that a RPG-CERBERUS protein complex that is involved in an exocytotic pathway mediating IT polarity growth which is driven by nuclear migration. One sentence summaryPuncta localization RPG-CERBERUS protein complex promote polarity growth of ITs driven by nuclear migration.

cell biology↗

bioRxiv2022

Non-aging despite high mutation rate - genomic insights into the evolution of Hydra

Hydra is a genus of freshwater polyps with remarkable regeneration abilities and a non-senescent phenotype under laboratory conditions. Thus, this animal is particularly interesting for aging research. Here, we gained insights into Hydras recent genetic evolution by genome sequencing of single cells and whole individuals. Despite its extreme longevity, Hydra does not show a lower somatic mutation rate than humans or mice. While we identify biological processes that have evolved under positive selection in animals kept in optimal laboratory conditions for decades, we found no signs of strong negative selection during this tiny evolutionary window. Interestingly, we observe the opposite pattern for the preceding evolution in the wild over a longer time period. Moreover, we found evidence that Hydra evolution in captivity was accompanied and potentially accelerated by loss of heterozygosity. Processes under positive selection in captive animals include pathways associated with Hydras simple nervous system, its nucleic acid metabolic process, cell migration, and hydrolase activity. Genes associated with organ regeneration, regulation of mRNA splicing, histone ubiquitination, and mitochondrial fusion were identified as highly conserved in the wild. Remarkably, several of the processes under strongest selection are closely related to those considered essential for the exapted, i. e. not brought about by natural selection, feature: Hydras non-aging.

evolutionary biology↗

bioRxiv2021

Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis

Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant non-malignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. We used an inhibitor of colony stimulating factor 1 receptor (CSF1R) to target TAMs at distinct stages of the metastatic cascade in preclinical breast-to-brain metastasis models and found that CSF1R inhibition leads to anti-tumor responses in prevention and intervention trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuro-inflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, combined blockade of CSF1R and STAT5 signaling led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.

cancer biology↗

bioRxiv2020

Status-dependent aging rates in long-lived, social mole-rats are shaped by HPA stress axis

Sexual activity and/or reproduction doubles life expectancy in the long-lived rodent genus Fukomys. To investigate the molecular mechanisms underlying this phenomenon, we analyzed a total of 636 RNA-seq samples across 15 tissues. This analysis suggests that the differences in life expectancy between reproductive and non-reproductive mole-rats are mainly caused by critical changes in the regulation of the hypothalamic-pituitary-adrenal stress axis, which we further substantiate with a series of independent evidence. In accordance with previous studies, the up-regulation of the proteasome and several so-called "anti-aging molecules", such as DHEA, is also linked with enhanced life expectancy. On the other hand, several our results oppose crucial findings in short-lived model organisms. For example, we found the up-regulation of the IGF1/GH axis and several other anabolic processes to be compatible with a considerable lifespan prolongation. These contradictions question the extent to which findings from short-lived species can be transferred to longer-lived ones.

genomics↗

bioRxiv2019

Mitohormetic effects of rotenone drastically depend on age

Hormesis refers to a biphasic intensity-dependent response to stressors where low-intensity or short-duration exposure to potentially noxious stressors induces long-lasting adaptations that have positive physiological effects [1]. It was proposed that life-extending interventions, such as calorie restriction, retard aging via their hormetic action [2]. More recently, it was shown that a transient burst of reactive oxygen species is required to induce the effects of calorie restriction [3], physical exercise [4], inhibition of the insulin/IGF-I pathway [5] and metformin [6]. We have previously shown that partial inhibition of complex I of the respiratory chain by a low dose of the poison rotenone (ROT) administered in middle age increases the lifespan and reverts the transcriptomic signature of aging in a vertebrate species [7], an example of a hormetic effect. Here, we asked whether ROT treatment started at young age induces larger effects on life-span and transcriptome.

pharmacology and toxicology↗

bioRxiv2018

Higher transcriptome stability during aging in long-lived giant mole-rats compared to short-lived rats

Many aging-associated physiological changes are known to come up in short- and long-lived species with a different trajectory and emerging evidence suggests that large parts of life history trait differences between species are based on inter-species variation in gene expression. Little information is yet available, however, about transcriptome changes during aging when comparing mammals with different lifespans. For this reason, we studied the transcriptomes of five tissues and two age cohorts in two similar sized rodent species with very different lifespans: rat (Rattus norvegicus) and giant mole-rat (Fukomys mechowii) with maximum lifespans of 3.8 and >20 years, respectively. Our results show that giant mole-rats exhibit higher transcriptome stability during aging than the rat. While well-known aging signatures (e.g. up-regulation of pro-inflammatory genes) were detected in all rat tissues, they showed up only in one giant mole-rat tissue. Furthermore, many differentially expressed genes that were found in both species, were regulated in opposite directions during aging. This suggests that expression changes that cause aging in short-lived species are counteracted in long-lived species. Taken together, transcriptome stability may be one key causal factor of the long life- and healthspan of giant mole-rats and maybe of African mole-rats in general.

systems biology↗

bioRxiv2017

Naked mole-rat transcriptome signatures of socially-suppressed sexual maturation and links of reproduction to aging

Naked mole-rats (NMRs) are eusocially organized in colonies. Although breeders carry the additional metabolic load of reproduction, they are extremely long-lived and remain fertile throughout their lifespan. Comparative transcriptome analysis of ten organs from breeders and non-breeders of the eusocial long-lived NMR and the polygynous shorter-lived guinea pig provide comprehensive and unbiased molecular evidence that sexual maturation in NMR is socially suppressed. After transition into breeders, transcriptomes are markedly sex-specific, show pronounced feedback signaling via gonadal steroids and have similarities to reproductive phenotypes in African cichlid fish. Further, NMRs show functional enrichment of status-related expression differences associated with aging. Lipid metabolism and oxidative phosphorylation - molecular networks known to be linked to aging - were identified among most affected gene sets. Further, a transcriptome pattern associated with longevity is reinforced in NMR breeders contradicting the disposable soma theory of aging and potentially contributing to their exceptional long life- and healthspan.

systems biology↗

bioRxiv2017

Long-lived rodents reveal signatures of positive selection in genes associated with lifespan and eusociality

The genetic mechanisms that determine lifespan are poorly understood. Most research has been done on short lived animals and it is unclear if these insights can be transferred to long-lived mammals like humans. Some African mole-rats (Bathyergidae) have life expectancies that are multiple times higher than similar sized and phylogenetically closely related rodents. We obtained genomic and transcriptomic data from 17 rodent species and systematically scanned eleven lineages associated with the evolution of longevity and eusociality for positively selected genes (PSGs). The set of 319 PSGs contains regulators of mTOR and is enriched in functional terms associated with (i) processes that are regulated by the mTOR pathway, e.g. translation, autophagy and mitochondrial biogenesis, (ii) the immune system and (iii) antioxidant defense. Analyzing gene expression of PSGs during aging in the long-lived naked mole-rat and up-regulation in the short-lived rat, we found a pattern fitting the antagonistic pleiotropy theory of aging.

evolutionary biology↗