Biology subjects

Reinert, S.

Publications and source records attributed to Reinert, S..

7 recordsLinked to original sources

bioRxiv2026

A cross-species single-cell epigenome kidney atlas identifies epithelial cells as a driver of epigenetic aging

Epigenetic aging is a hallmark of chronic diseases, arising from sustained injuries and unresolved repairs. To investigate cell-type-specific epigenetic alterations, we built a cross-species single-cell multi-omics atlas of DNA methylomes, chromatin accessibilities, and transcriptomes on healthy, injured (human) and aging (mouse) kidneys. We identified accelerated epigenetic aging dominated by tubular epithelia in diseased kidneys. The pathological state mirrors transcriptional trajectories observed in normal aging, driven by the preferential dysregulation of lineage-specific genes lacking CpG islands. Spatially, these epigenetic changes mapped to pathological niches of failed repair. Co-profiling of single-cell DNA methylation and 3D genome architecture revealed that epithelial repair states in disease undergo significant higher-order genome reorganizations, activating genes associated with renal decline. Our findings demonstrate that epithelial aging is driven by a collapse of 3D chromatin structure and local methylome integrity, which silences cell identity and promotes a non-resolving repair state.

genomics↗

bioRxiv2025

Cellular and Spatial Drivers of Unresolved Injury and Functional Decline in the Human Kidney

Building upon a foundational Human Kidney resource, we present a comprehensive multi-modal atlas that defines spatially resolved versus unresolved repair states and mechanisms in human kidney disease. Homeostatic interactions between injured kidney epithelium and its surrounding milieu determine successful repair outcomes, while pathogenic signaling promotes unresolved inflammation and fibrosis leading to chronic disease. We integrated multiple single-cell and spatial modalities across [~]700 samples from >350 patients ([~]250 research biopsies), analyzing [~]1.7 million cells alongside complementary mouse multi-omic profiles spanning acute-to-chronic injury and aging (>300,000 cells) and spatial transcriptomic analysis of >150 human biopsies. This cross-species atlas delineates functional pathways and druggable targets across the nephron and defines gene regulatory networks and chromatin landscapes governing tubular, fibroblast, and immune cell transitions from injury to either recovery or failed repair states. We identified distinct cellular states associated with specific pathological features that show dynamic distributions between acute kidney injury (AKI) and chronic kidney disease (CKD), organized within unique spatial niches that reveal progression mechanisms from early injury to unresolved disease. Gene regulatory analyses prioritized key transcription factor activities (SOX4, SOX9, NFKB1, REL, KLFs) and their target networks establishing disease states and tissue microenvironments. These regulatory programs were directly linked to clinical outcomes, identifying molecular signatures of recovery and secreted biomarkers predictive of AKI-to-CKD progression, providing a key resource for therapeutic development and precision medicine approaches in kidney disease.

molecular biology↗

bioRxiv2025

A mechanistic theory of planning in prefrontal cortex

Planning is critical for adaptive behaviour in a changing world, because it lets us anticipate the future and adjust our actions accordingly. While prefrontal cortex is crucial for this process, it remains unknown how planning is implemented in neural circuits. Prefrontal representations were recently discovered in simpler sequence memory tasks, where different populations of neurons represent different future time points. We demonstrate that combining such representations with the ubiquitous principle of neural attractor dynamics allows circuits to solve much richer problems including planning. This is achieved by embedding the environment structure directly in synaptic connections to implement an attractor network that infers desirable futures. The resulting 'spacetime attractor' excels at planning in challenging tasks known to depend on prefrontal cortex. Recurrent neural networks trained by gradient descent on such tasks learn a solution that precisely recapitulates the spacetime attractor - in representation, in dynamics, and in connectivity. Analyses of networks trained across different environment structures reveal a generalisation mechanism that rapidly reconfigures the world model used for planning, without the need for synaptic plasticity. The spacetime attractor is a testable mechanistic theory of planning. If true, it would provide a path towards detailed mechanistic understanding of how prefrontal cortex structures adaptive behaviour.

neuroscience↗

bioRxiv2025

Sensorimotor remapping drives task specialization in prefrontal cortex

The prefrontal cortex (PFC) plays a key role in flexible, context-dependent decision-making. Yet, the population-level mechanisms that support this flexibility remain unclear: is there a generalist neural population involved in representing useful information across tasks, or are representations distributed over multiple modules of task-specialized subpopulations? Here, we investigate whether the population structure modularity in medial prefrontal cortex (mPFC) increases with sensorimotor remapping between task rules in two different paradigms. In a paradigm where all stimuli were remapped, we found a highly modular structure with two task-specialized subpopulations and one generalist. In a different paradigm where only half of the stimuli were remapped, modularity decreased but remained significant. Based on predictions drawn from a recurrent neural network fitted to experimental data, we propose that a gain modulation by global inhibition of mPFC can explain how task-specialized neurons emerge to varying degrees in each paradigm.

neuroscience↗

bioRxiv2023

Carbon usage in yellow-fleshed Manihot esculenta storage roots shifts from starch biosynthesis to cell wall and raffinose biosynthesis via the myo-inositol pathway

Cassava is a crucial staple crop for smallholder farmers in tropical Asia and Sub-Saharan Africa. Although high yield remains the top priority for farmers, the significance of nutritional values has increased in cassava breeding programs. A notable negative correlation between provitamin A and starch accumulation poses a significant challenge for breeding efforts. The negative correlation between starch and carotenoid levels in conventional and genetically modified cassava plants implies the absence of a direct genomic connection between the two traits. The competition among various carbon pathways seems to account for this relationship. In this study, we conducted a thorough analysis of 49 African cassava genotypes with varying levels of starch and provitamin A. Our goal was to identify factors contributing to differential starch accumulation. With the carotenoid levels of the varieties considered as a confounding effect on starch production, we found that yellow and white-fleshed storage roots did not differ significantly in most measured components of starch or de novo fatty acid biosynthesis. However, genes and metabolites associated with myo-inositol synthesis and cell wall component production were substantially enriched in high provitamin A genotypes. These results indicate that yellow-fleshed cultivars, in comparison to their white-fleshed counterparts, direct more carbon towards the synthesis of raffinose and cell wall components, a finding that is supported by a significant rise in the starch-free residue to total dry yield ratio in yellow storage roots versus white storage roots. Our findings enhance comprehension of the biosynthesis of starch and carotenoids in the storage roots of cassava.

plant biology↗

bioRxiv2021

Global genetic heterogeneity in adaptive traits

Understanding the genetic architecture of complex traits is a major objective in biology. The standard approach for doing so is genome-wide association studies (GWAS), which aim to identify genetic polymorphisms responsible for variation in traits of interest. In human genetics, consistency across studies is commonly used as an indicator of reliability. However, if traits are involved in adaptation to the local environment, we do not necessarily expect reproducibility. On the contrary, results may depend on where you sample, and sampling across a wide range of environments may decrease the power of GWAS because of increased genetic heterogeneity. In this study, we examine how sampling affects GWAS for a variety of phenotypes in the model plant species Arabididopsis thaliana. We show that traits like flowering time are indeed influenced by distinct genetic effects in local populations. Furthermore, using gene expression as a molecular phenotype, we show that some genes are globally affected by shared variants, while others are affected by variants specific to subpopulations. Remarkably, the former are essentially all cis-regulated, whereas the latter are predominately affected by trans-acting variants. Our result illustrate that conclusions about genetic architecture can be incredibly sensitive to sampling and population structure.

evolutionary biology↗

bioRxiv2020

Heritable associations with microbial communities are essential for necrotrophic pathogen resistance

Host-microbe interactions are increasingly recognized as important drivers of organismal health, growth, longevity, and community-scale ecological processes. However, less is known about how genetic variation affects hosts associated microbiomes and downstream phenotypes. We demonstrate that sunflower (Helianthus annuus) harbors substantial, heritable variation in microbial communities under field conditions. We show that microbial communities explain up to 77.5% of the heritable variation in resistance to root infection caused by the necrotrophic pathogen Sclerotinia sclerotiorum, and that plants grown in sterilized soil showed almost complete elimination of pathogen resistance. Association mapping revealed 69 genetic locations related to microbial abundance and Sclerotinia resistance. Although the genetic architecture is complex and quantitative, we have, in large part, elucidated previously unexplained genetic variation for resistance to this pathogen. This suggests new targets for plant breeding and demonstrates the potential for heritable microbial associations to play important roles in defense in natural and human-altered environments.

ecology↗