TY  - JOUR
AU  - Kühlwein, Julia
AU  - Ruf, Wolfgang
AU  - Kandler, Katharina
AU  - Witzel, Simon
AU  - Lang, Christina
AU  - Mulaw, Medhanie A
AU  - Ekici, Arif B
AU  - Weishaupt, Jochen H
AU  - Ludolph, Albert C
AU  - Grozdanov, Veselin
AU  - Danzer, Karin M
TI  - ALS is imprinted in the chromatin accessibility of blood cells.
JO  - Cellular and molecular life sciences
VL  - 80
IS  - 5
SN  - 1420-682X
CY  - Cham (ZG)
PB  - Springer International Publishing AG
M1  - DZNE-2023-00495
SP  - 131
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Epigenesis, Genetic
KW  - Chromatin
KW  - Genetic Predisposition to Disease
KW  - Neurodegenerative Diseases: genetics
KW  - Blood Cells: metabolism
KW  - Blood Cells: pathology
KW  - Chromatin remodeling (Other)
KW  - Epigenome (Other)
KW  - Integrated analysis (Other)
KW  - Motor neuron disease (Other)
KW  - Regulatory elements (Other)
KW  - Single-nuclei sequencing (Other)
KW  - Chromatin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37095391
C2  - pmc:PMC10126052
DO  - DOI:10.1007/s00018-023-04769-w
UR  - https://pub.dzne.de/record/257780
ER  -