Biology subjects

Ruje, L.

Publications and source records attributed to Ruje, L..

4 recordsLinked to original sources

bioRxiv2024

Rapid long-range synaptic remodeling in hyperacute ischemic stroke

Physiological mechanisms of the key hyperacute (0-24 hours) stage of stroke remain incompletely understood, hampering development of new stroke therapies. Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders. Here, we describe rapid region-specific patterns of synaptic remodeling in stroke, arising within 4 hours of onset. While the ischemic core exhibits profound structural and functional synaptic decline, synapses in the mildly ischemic penumbra largely retain their structure, decreasing synaptic function. Conversely, synapses in the contralateral cortex across the brain show widespread structural and functional increase. Mechanistically, hyperacute stroke triggers synaptic recruitment of NMDA receptors in the ischemic core and penumbra, while NMDA receptor blockade exacerbates structural synaptic decline in the penumbra and abolishes contralateral synaptic enhancement. Proteomic analysis confirms cross-brain synaptic strengthening and reveals emergence of metabolic rearrangement in the penumbra, while RNAseq indicates broad downregulation of synaptic gene expression in the penumbra. These findings identify brain-wide homeostatic synaptic rebalancing as a potential mechanism for rapid-response functional compensation in early stroke, highlighting the extent of brain resilience to acute perturbation. HighlightsO_LIStroke induces rapid long-range synaptic enhancement in the contralateral hemisphere C_LIO_LINMDAR signaling orchestrates short and long-range synaptic remodeling in stroke C_LIO_LIProteomics and RNAseq reveal details of region-specific synaptic remodeling C_LI eTOC blurbWhat happens to synaptic communication across the brain during the first hours of stroke is unclear. We find that while synapses at the center of the stroke quickly fall apart, those in the surrounding area are protected and those in the opposite hemisphere are rapidly strengthened by the activity of NMDA-type glutamate receptors.

neuroscience↗

bioRxiv2024

CTCF binding landscape is established by the epigenetic status of the nucleosome, well-positioned relative to CTCF motif orientation

CTCF binding sites serve as anchors for the 3D chromatin architecture in vertebrates. The functionality of these anchors is influenced by the residence time of CTCF on chromatin, which is determined by its binding affinity and its interactions with nucleosomes and other chromatin-associated factors. In this study, we demonstrate that CTCF occupancy is driven by CTCF motifs, strategically positioned at the entry sides of a well-positioned nucleosome, such that, upon binding, the N-terminus of CTCF is oriented towards the nucleosome. We refer to this nucleosome as the CTCF priming nucleosome (CPN). CTCF recognizes its binding sites if they are not methylated. It can then displace the CPN, provided the nucleosome is not marked by CpG methylation or repressive histone modifications. Under these permissive conditions, the N-terminus of CTCF recruits SMARCA5 to reposition the CPN downstream, thereby creating nucleosome-free regions that enhance CTCF occupancy and cohesin stalling. In contrast, when CPNs carry repressive epigenetic marks, CTCF binding is transient, without nucleosome displacement or chromatin opening. In such cases, cohesin is not effectively retained at CTCF binding sites. We propose that the epigenetic status of CPNs shapes cell-specific CTCF binding patterns, ensuring the maintenance of chromatin architecture throughout the cell cycle. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/614770v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@105f34eorg.highwire.dtl.DTLVardef@1a88a82org.highwire.dtl.DTLVardef@1d90f2org.highwire.dtl.DTLVardef@1170e49_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Nucleosome reorganisation in breast cancer tissues

Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. Here we have generated high resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with [~]20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. In addition, tumour tissues were characterised by a 5-10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. These effects were correlated with gene activity, DNA sequence repeats abundance, differential DNA methylation and binding of linker histone variants H1.4 and H1X. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient stratification and monitoring using liquid biopsies.

genomics↗

bioRxiv2022

Nucleosome repositioning in chronic lymphocytic leukaemia

The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we performed a systematic comparison of high-resolution nucleosome maps in peripheral-blood B-cells from patients with chronic lymphocytic leukaemia (CLL) and healthy individuals at single base pair resolution. Our investigation uncovered significant changes of both nucleosome positioning and packing in CLL. Globally, the spacing between nucleosomes (the nucleosome repeat length, NRL) was shortened in CLL. This effect was stronger in the more aggressive IGHV-unmutated than IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites were linked to active chromatin remodelling and reduced DNA methylation. Nucleosomes lost or gained in CLL in comparison with non-malignant B-cells marked differential binding of 3D chromatin organisers such as CTCF as well as immune response-related transcription factors, allowing delineating epigenetic mechanisms affected in CLL. Furthermore, patients could be better assigned to CLL subtypes according to nucleosome occupancy at cancer-specific sites than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome positioning changes detected in our study, like the reduced NRL, can be exploited for liquid biopsy applications based on cell-free DNA to monitor disease progression.

genomics↗