Publikasjoner
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Mirzac, Daniela; Glaser, Martin B.; Kreis, Svenja L.; Ringel, Florian; Bange, Manuel & Herz, Damian M.
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(2025).
Cortical Single-Cell Primers of Abnormal Brain Activity in Parkinson’s Disease.
Research.
ISSN 2096-5168.
8.
doi:
10.34133/research.0863.
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Abnormal brain oscillatory activity is a well-established hallmark of bradykinesia and motor impairment in Parkinson’s disease (PD), yet its molecular underpinnings remain unclear. To address this gap, we analyzed over 100,000 single-cell RNA transcriptomes from fresh dorsolateral prefrontal cortex tissue of individuals with PD and non-PD controls, undergoing deep brain stimulation—2 cohorts, which open up an unprecedent window to the characterization of human cortical brain tissue, aiming to uncover the molecular mechanisms of abnormal brain oscillatory activity in PD. Fresh brain tissue samples offer a unique opportunity to precisely elucidate the molecular underpinnings of known, clinically relevant electrophysiological hallmarks of neurodegeneration, which can be used to inform targeted therapeutic strategies. We depicted in microglia and astrocytes enrichment of mitochondrial electron transport and oxidative phosphorylation pathways, which were directly linked to the increase of pathological brain activity and the decrease of prokinetic brain activity. Additionally, the abnormal phase–amplitude coupling of beta–gamma brain activity was related to the dysfunction of oligodendrocyte precursor cells and inflammasome activation mediated by lymphocyte-driven adaptive immunity. We identified a distinct set of dysregulated genes from the mitogen-activated protein kinase phosphorylation pathways, mitochondrial electron transport at the intersection of neuroinflammation and neurodegeneration, suggesting pivotal roles in PD pathology. This unique dataset provides unprecedented insights into the immune and metabolic dysregulation underlying PD, offering a mechanistic framework for understanding invasive transcriptomic biomarkers related to prokinetic and pathologic brain activity in PD.
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Rossini, Roberto; Oshaghi, Mohammadsaleh; Nekrasov, Maxim; Bellanger, Aurélie Nathalie Pascale; Domaschenz, Renae & Dijkwel, Yasmin
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(2025).
Loss of multilevel 3D genome organization during breast cancer progression.
Genome Research.
ISSN 1088-9051.
s. 1–18.
doi:
10.1101/gr.280791.125.
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Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we have conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that although the fundamental properties of topologically associating domains (TADs) are overall maintained, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD–TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on Chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on Chromosome 10. This insertion is accompanied by the formation of de novo enhancer contacts and activation of MYC , illustrating how structural genomic variants can alter the 3D genome during oncogenesis. In summary, our findings provide evidence for the loss of genome organization at multiple scales during breast cancer progression, revealing novel relationships between genome 3D structure and oncogenic processes.
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Nahali, Negar; Oshaghi, Mohammadsaleh & Paulsen, Jonas
(2024).
Modeling properties of chromosome territories using polymer filaments in diverse confinement geometries.
Chromosome Research.
ISSN 0967-3849.
32.
doi:
10.1007/s10577-024-09753-z.
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Interphase chromosomes reside within distinct nuclear regions known as chromosome territories (CTs). Recent observations from Hi-C analyses, a method mapping chromosomal interactions, have revealed varied decay in contact probabilities among different chromosomes. Our study explores the relationship between this contact decay and the particular shapes of the chromosome territories they occupy. For this, we employed molecular dynamics (MD) simulations to examine how confined polymers, resembling chromosomes, behave within different confinement geometries similar to chromosome territory boundaries. Our simulations unveil so far unreported relationships between contact probabilities and end-to-end distances varying based on different confinement geometries. These findings highlight the crucial impact of chromosome territories on shaping the larger-scale properties of 3D genome organization. They emphasize the intrinsic connection between the shapes of these territories and the contact behaviors exhibited by chromosomes. Understanding these correlations is key to accurately interpret Hi-C and microscopy data, and offers vital insights into the foundational principles governing genomic organization.
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Publisert
7. apr. 2022 11:09
- Sist endret
7. apr. 2022 11:09