Biology subjects

Wahlestedt, C.

Publications and source records attributed to Wahlestedt, C..

5 recordsLinked to original sources

bioRxiv2025

Exercise-induced DNA damage response and memory formation in mice

This study reveals that acute aerobic exercise enhances memory formation through a controlled DNA damage mechanism, offering crucial insights into Alzheimers disease (AD) prevention. This work challenges the traditional view that DNA damage is inherently harmful, demonstrating that minor, reversible DNA single-strand breaks (SSBs) induced by exercise serve as necessary primers for memory consolidation - a mechanism that may be impaired in AD pathogenesis. AD affects 1 in 9 adults over 65, with ~95% being late-onset cases where up to 40% of risk factors are modifiable through lifestyle interventions like exercise. While exercise demonstrably lowers AD risk, underlying mechanisms remain unclear. This study provides a missing mechanistic link by showing how exercise-induced DNA damage repair systems could counteract the DNA damage accumulation and repair dysregulation that are established hallmarks of brain aging and AD. In data presented herein, young mice showed significantly higher SSB rates in active genomic regions compared to aged mice, suggesting the decline of a protective mechanism (i.e., hormesis) with aging - potentially explaining increased AD susceptibility in older adults. The present study also suggests that exercise-induced SSBs are not random cellular damage but precisely targeted events that occur at genes essential for neuroplasticity, synaptic function, and memory formation. These breaks activate PARP1 (Poly ADP ribose polymerase 1), a crucial DNA damage sensor that simultaneously initiates repair processes while facilitating transcriptional programs necessary for memory consolidation. This mechanism may represent how exercise "primes" the brain against the pathological DNA damage accumulation seen in AD. In support of this, in behavioral experiments, a single exercise bout converted sub-threshold learning into robust long-term memory formation. This memory enhancement correlated with upregulation of both neurotrophic genes (BDNF, Fos) and DNA repair enzymes (PARP1, PARP2), demonstrating coordinated damage-repair processes that appear compromised in AD. We identify HPF1 as a critical cofactor enabling PARP1 to perform trans-ADP-ribosylation of histones, linking DNA damage sensing to epigenetic chromatin remodeling required for memory-related gene expression. This pathway represents a novel therapeutic target for AD, as restoring efficient DNA repair mechanisms might slow or prevent memory loss.

neuroscience↗

bioRxiv2024

Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling

A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growth in vivo, while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, including CYTOR - which was leukocyte-associated (FDR = 4.9 x10-7). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 x 10-8), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 x 10-5). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in vivo. Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways. One Sentence SummaryWe used an optimised transcriptomic strategy to identify a set of ncRNA genes regulated during skeletal muscle hypertrophy in one hundred and forty-four people, with network modelling and spatial imaging providing biological context.

bioinformatics↗

bioRxiv2023

Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation, and that post-methamphetamine microglial repopulation attenuates drug-seeking following a 21-day period of abstinence. In contrast, microglial depletion during abstinence did not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/563168v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@640bf6org.highwire.dtl.DTLVardef@4d5f5forg.highwire.dtl.DTLVardef@1b08864org.highwire.dtl.DTLVardef@ca80fa_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2017

SUPERmerge: ChIP-Seq Coverage Island Analysis Algorithm For Broad Histone Marks

SUPERmerge is a ChIP-seq read pileup analysis and annotation algorithm for investigating alignment (BAM) files of diffuse histone modification ChIP-seq datasets with broad chromatin domains at a single base pair resolution level. SUPERmerge allows flexible regulation of a variety of read pileup parameters, thereby revealing how read islands aggregate into areas of coverage across the genome and what annotation features they map to within individual biological replicates. SUPERmerge is especially useful for investigating low sample size ChIP-seq experiments in which epigenetic histone modifications (e.g., H3K9me1, H3K27me3) result in inherently broad peaks with a diffuse range of signal enrichment spanning multiple consecutive genomic loci and annotated features.

bioinformatics↗

bioRxiv2016

geneXtendeR: R/Bioconductor package for functional annotation of histone modification ChIP-seq data in a 3D genome world

MotivationDifferent ChIP-seq peak callers often produce different output results from the same input. Since different peak callers are known to produce differentially enriched peaks with a large variance in peak length distribution and total peak count, accurately annotating peak lists with their nearest genes can be an arduous process. Functional genomic annotation of histone modification ChIP-seq data can be a particularly challenging task, as chromatin marks that have inherently broad peaks with a diffuse range of signal enrichment (e.g., H3K9me1, H3K27me3) differ significantly from narrow peaks that exhibit a compact and localized enrichment pattern (e.g., H3K4me3, H3K9ac). In addition, varying degrees of tissue-dependent broadness of an epigenetic mark can make it difficult to accurately and reliably link sequencing data to biological function. Thus, there exists an unmet need to develop a software program that can precisely tailor the computational analysis of a ChIP-seq dataset to the specific peak coordinates of the data and its surrounding genomic features.\n\nResultsgeneXtendeR optimizes the functional annotation of ChIP-seq peaks by exploring relative differences in annotating ChIP-seq peak sets to variable-length gene bodies. In contrast to prior techniques, geneXtendeR considers peak annotations beyond just the closest gene, allowing users to investigate peak summary statistics for the first-closest gene, second-closest gene, ..., nth-closest gene whilst ranking the output according to biologically relevant events and iteratively comparing the fidelity of peak-to-gene overlap across a user-defined range of upstream and downstream extensions on the original boundaries of each genes coordinates. We tested geneXtendeR on 547 human transcription factor ChIP-seq ENCODE datasets and 198 human histone modification ChIP-seq ENCODE datasets, providing the analysis results as case studies.\n\nAvailabilityThe geneXtendeR R/Bioconductor package (including detailed introductory vignettes) is available under the GPL-3 Open Source license and is freely available to download from Bioconductor at: https://bioconductor.org/packages/geneXtendeR/\n\nAuthor summarygeneXtendeR makes functional annotation of ChIP-seq data more robust and precise, regardless of peak variability attributable to parameter tuning or peak caller algorithmic differences. Since different ChIP-seq peak callers produce differentially enriched peaks with large variance in peak length distribution and total peak count, annotating peak lists with their nearest genes can often be a noisy process where an adjacent second or third-closest gene may constitute a more viable biological candidate, e.g., during cases of linked genes that are located close to each other. As such, the goal of geneXtendeR is to robustly link differentially enriched peaks with their respective genes, thereby aiding experimental follow-up and validation in designing primers for a set of prospective gene candidates during qPCR.

bioinformatics↗