Biology subjects

Hetzer, J.

Publications and source records attributed to Hetzer, J..

5 recordsLinked to original sources

bioRxiv2026

Climate change intensifies rapid genomic selection beyond the ancestral niche of Fagus sylvatica

As climate change accelerates, the persistence of long-lived organisms increasingly depends on their capacity to adapt in situ. While phenotypic plasticity provides an immediate buffer, it remains uncertain whether forest trees can evolve rapidly enough to track shifting climatic niches. Here, we investigate the adaptive potential of European beech (Fagus sylvatica L.), a keystone temperate species, by leveraging different growth classes as a quasi-time-series. This approach allows us to compare growth classes established under the relatively stable climate of the early 20th century against those regenerating under contemporary warming (+1.1{degrees}C global mean temperature increase). Integrating pool-seq data from three growth classes across 43 sites in Germany with satellite-derived environmental stress indicators, we characterised past, current and projected future climate-driven selection. We detected rapid, genome-wide selective sweeps between the oldest and youngest growth classes, particularly in sites already exceeding their historical climatic niche (defined as the 95% confidence interval of pre-warming conditions). Notably, selection signatures have shifted over time: while older classes show signatures related to biotic interactions, younger cohorts exhibit intense selection on genes managing abiotic heat and drought stress. In the warmest regions, we estimated exceptionally high selection coefficients (s{approx}2), suggesting intense selection where beech trees exceed their ancestral niche. In older growth classes, distance and geology account for genetic differences between populations but in young growth classes climate is the primary factor, highlighting the importance of climate change. However, predictive modelling reveals a critical threshold to this resilience. While adaptive potential appears sufficient to maintain population persistence under low-emission scenarios (SSP1-2.6), high-emission trajectories (SSP5-8.5) are projected to rapidly outpace the species evolutionary capacity. These findings demonstrate that while trees can undergo remarkably rapid genomic shifts, the sheer velocity of unmitigated climate change threatens to exceed the fundamental limits of forest adaptation.

evolutionary biology↗

bioRxiv2024

Modulation of the ATP-adenosine signaling axis combined with radiotherapy facilitates anti-cancer immunity in brain metastasis

The immunosuppressive microenvironment in the brain poses a major limitation to successful therapy for brain metastases. Here we report that blockade of the ATP-to-adenosine-converting enzymes CD39 and CD73 and the adenosine receptor A2AR in combination with radiotherapy attenuates tumor progression in a breast-to-brain metastasis model by facilitating anti-cancer immunity. Immunophenotyping revealed loss of exhausted T cells and higher abundance of anti-cancer effector T cell populations. This effect was accompanied by a decrease of immunosuppressive lipid-laden macrophages and an expansion of CD14CD33high macrophages associated with antigen presentation. Analyses of human brain metastases samples supports a role of the ATP-adenosine signaling axis in modulating tumor inflammation and identified expression of CD39 and adenosine deaminase as predictive markers for patient survival and/or immune infiltration. Our findings demonstrate that the adenosine axis represents a druggable pathway to achieve local immunomodulation and treatment response, opening a new therapeutic avenue for brain metastases patients.

cancer biology↗

bioRxiv2023

Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPAR alpha and PCK1 action in hepatocytes

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents/ameliorates NASH and fibrosis as well as reduces subsequent HCC development without affecting total calorie intake. The timing, length and number of fasting cycles as well as the type of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteomic, transcriptomic and metabolomic analyses identified that PPAR and glucocorticoid receptor (GR)-PCK1 act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis whilst suppressing anabolic lipogenesis. In line, PPAR targets and PCK1 were reduced in human NASH. Additionally, dynamic [18F]FDG-PET analysis in vivo revealed increased [18F]FDG uptake/retention and enhanced gluconeogenesis in the liver upon fasting (in accordance with PPAR and GR-PCK1 activation) when assessed by compartmental modelling. Hepatocyte-specific GR deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Notably, PPAR agonist pemafibrate recapitulated key aspects of hepatic fasting signalling at a molecular level. Therefore, IF or pharmacological mimetics of the PPAR and/or GR-PCK1 axis could be a viable intervention against NASH and subsequent liver cancer. One-Sentence SummaryIntermittent fasting protects against fatty liver disease and liver cancer through concerted PPAR and GR-PCK1 action in hepatocytes.

cancer biology↗

bioRxiv2023

Phenotypic drought stress prediction of European beech (Fagus sylvatica) by genomic prediction and remote sensing

Current climate change species response models usually not include evolution. We integrated remote sensing with population genomics to improve phenotypic response prediction to drought stress in the key forest tree European beech (Fagus sylvatica L.). We used whole-genome sequencing of pooled DNA from natural stands along an ecological gradient from humid-cold to warm-dry climate. We phenotyped stands for leaf area index (LAI) and moisture stress index (MSI) for the period 2016-2022. We predicted this data with matching meteorological data and a newly developed genomic population prediction score in a Generalised Linear Model. Model selection showed that addition of genomic prediction decisively increased the explanatory power. We then predicted the response of beech to future climate change under evolutionary adaptation scenarios. A moderate climate change scenario would allow persistence of adapted beech forests, but not worst-case scenarios. Our approach can thus guide mitigation measures, such as allowing natural selection or proactive evolutionary management.

evolutionary biology↗

bioRxiv2021

Epithelial cells of the intestine acquire cell-intrinsic inflammation signatures during ageing

During ageing, cell-intrinsic and extrinsic factors lead to the decline of tissue function and organismal health. Disentangling these factors is important for developing effective strategies to prolong organismal healthspan. Here, we addressed this question in the mouse intestinal epithelium, which forms a dynamic interface with its microenvironment and receives extrinsic signals affecting its homeostasis and tissue ageing. We systematically compared transcriptional profiles of young and aged epithelial cells in vivo and ex vivo in cultured intestinal organoids. We found that all cell types of the aged epithelium exhibit an inflammation phenotype, which is marked by MHC class II upregulation and most pronounced in enterocytes. This was accompanied by elevated levels of the immune tolerance markers PD-1 and PD-L1 in the aged tissue microenvironment, indicating dysregulation of immunological homeostasis. Intestinal organoids from aged mice still showed an inflammation signature after weeks in culture, which was concurrent with increased chromatin accessibility of inflammation-associated loci. Our results reveal a cell-intrinsic, persistent inflammation phenotype in aged epithelial cells, which might contribute to systemic inflammation observed during ageing.

genomics↗