Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [ATAC-Seq]
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ABSTRACT: Loss of the nuclear RNA binding protein TAR DNA binding protein-43 (TDP-43) into cytoplasmic aggregates is the strongest correlate to neurodegeneration in amyotrophic lateral sclerosis and frontotemporal degeneration. The molecular changes associated with the loss of nuclear TDP-43 in human tissues are not entirely known. Using a novel subcellular fractionation and fluorescent activated cell sorting method to enrich for diseased neuronal nuclei without TDP-43 from post-mortem FTD-ALS human brain, we characterized the effects of TDP-43 loss on the transcriptome and chromatin accessibility. Nuclear TDP-43 loss is associated with gene expression changes that affect RNA processing, nucleocytoplasmic transport, histone processing and DNA damage. Loss of nuclear TDP-43 was also associated with chromatin decondensation around long interspersed nuclear elements (LINEs) and increased LINE1 DNA content. Moreover, loss of TDP-43 leads to increased retrotransposition that can be inhibited with antiretroviral drugs, suggesting that TDP-43 neuropathology is associated with altered chromatin structure including decondensation of LINEs.
ORGANISM(S): Homo sapiens
PROVIDER: GSE126541 | GEO | 2019/03/15
REPOSITORIES: GEO
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