Journal Article

DZNE-2023-00495

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ALS is imprinted in the chromatin accessibility of blood cells.

Kühlwein, J.Extern* ; Ruf, W.Extern* ; Kandler, K. ; Witzel, S.Extern* ; Lang, C.Extern* ; Mulaw, M. A. ; Ekici, A. B. ; Weishaupt, J. H.Extern* ; Ludolph, A. C.DZNE* ; Grozdanov, V.Extern* ; Danzer, K. M. (Last author)DZNE*

2023
Springer International Publishing AG Cham (ZG)

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Please use a persistent id in citations: doi:10.1007/s00018-023-04769-w

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a complex and incurable neurodegenerative disorder in which genetic and epigenetic factors contribute to the pathogenesis of all forms of ALS. The interplay of genetic predisposition and environmental footprints generates epigenetic signatures in the cells of affected tissues, which then alter transcriptional programs. Epigenetic modifications that arise from genetic predisposition and systemic environmental footprints should in theory be detectable not only in affected CNS tissue but also in the periphery. Here, we identify an ALS-associated epigenetic signature ('epiChromALS') by chromatin accessibility analysis of blood cells of ALS patients. In contrast to the blood transcriptome signature, epiChromALS includes also genes that are not expressed in blood cells; it is enriched in CNS neuronal pathways and it is present in the ALS motor cortex. By combining simultaneous ATAC-seq and RNA-seq with single-cell sequencing in PBMCs and motor cortex from ALS patients, we demonstrate that epigenetic changes associated with the neurodegenerative disease can be found in the periphery, thus strongly suggesting a mechanistic link between the epigenetic regulation and disease pathogenesis.

Keyword(s): Humans (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Epigenesis, Genetic (MeSH) ; Chromatin (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Neurodegenerative Diseases: genetics (MeSH) ; Blood Cells: metabolism (MeSH) ; Blood Cells: pathology (MeSH) ; Chromatin remodeling ; Epigenome ; Integrated analysis ; Motor neuron disease ; Regulatory elements ; Single-nuclei sequencing ; Chromatin

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Contributing Institute(s):

1. Mechanisms of Propagation (AG Danzer)
2. Clinical Study Center Ulm (Clinical Study Center Ulm)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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