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Transcriptomic Changes Due to Cytoplasmic TDP-43 Expression Reveal Dysregulation of Histone Transcripts and Nuclear Chromatin.

TitleTranscriptomic Changes Due to Cytoplasmic TDP-43 Expression Reveal Dysregulation of Histone Transcripts and Nuclear Chromatin.
Publication TypeJournal Article
Year of Publication2015
AuthorsAmlie-Wolf, A, Ryvkin, P, Tong, R, Dragomir, I, Suh, ER, Xu, Y, Van Deerlin, VM, Gregory, BD, Kwong, LK, Trojanowski, JQ, Lee, VM-Y, San Wang, L-, Lee, EB
JournalPLoS One
Date Published2015
Keywords3' Untranslated Regions, Animals, Cell Nucleus, Chromatin, Computational Biology, Cytoplasm, DNA-Binding Proteins, Gene Expression Profiling, Gene Knockdown Techniques, Histones, Humans, Mice, Mice, Transgenic, Nuclear Localization Signals, Reproducibility of Results, RNA Splicing, Sequence Deletion, Transcriptome

TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display dramatic changes in gene expression as measured by microarray, suggesting that cytoplasmic TDP-43 may be associated with a toxic gain-of-function. Here, we analyze new RNA-sequencing data from the ΔNLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice to investigate further the dysregulation of gene expression in the ΔNLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3' untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.

Alternate JournalPLoS ONE
PubMed ID26510133
PubMed Central IDPMC4624943
Grant ListR01-GM099962 / GM / NIGMS NIH HHS / United States
K08-AG039510 / AG / NIA NIH HHS / United States
R01 GM099962 / GM / NIGMS NIH HHS / United States
U24-AG041689 / AG / NIA NIH HHS / United States
P01-AG017586 / AG / NIA NIH HHS / United States