Amlie-Wolf, Alexandre

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2015 - 20162
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  • Publication
    Transcriptomic Changes Due to Cytoplasmic TDP-43 Expression Revel Dysregulation of Histone Transcripts and Nuclear Chromatin
    (2015-01-01) Amlie-Wolf, Alexandre; Ryvkin, Paul; Tong, Rui; Suh, EunRan; Xu, Yan; Van Deerlin, Vivianna M; Gregory, Brian D; Trojanowski, John Q; Lee, Virginia Man-Yee; Wang, Li-San; Lee, Edward B; Dragomir, Isabelle; Kwong, Linda K
    AR 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.
  • Publication
    DASHR: Database of Small Human Noncoding RNAs
    (2016-01-01) Leung, Yuk Y; Kuksa, Pavel P; Amlie-Wolf, Alexandre; Valladares, Otto; Ungar, Lyle H; Kannan, Sampath; Gregory, Brian D; Wang, Li-San
    Small non-coding RNAs (sncRNAs) are highly abundant RNAs, typically long, that act as key regulators of diverse cellular processes. Although thousands of sncRNA genes are known to exist in the human genome, no single database provides searchable, unified annotation, and expression information for full sncRNA transcripts and mature RNA products derived from these larger RNAs. Here, we present the Database of small human noncoding RNAs (DASHR) . DASHR contains the most comprehensive information to date on human sncRNA genes and mature sncRNA products. DASHR provides a simple user interface for researchers to view sequence and secondary structure, compare expression levels, and evidence of specific processing across all sncRNA genes and mature sncRNA products in various human tissues. DASHR annotation and expression data covers all major classes of sncRNAs including microRNAs (miRNAs), Piwi-interacting (piRNAs), small nuclear, nucleolar, cytoplasmic (sn-, sno-, scRNAs, respectively), transfer (tRNAs), and ribosomal RNAs (rRNAs). Currently, DASHR (v1.0) integrates 187 smRNA high-throughput sequencing (smRNA-seq) datasets with over 2.5 billion reads and annotation data from multiple public sources. DASHR contains annotations for ~48,000 human sncRNA genes and mature sncRNA products, 82% of which are expressed in one of more of the curated tissues. DASHR is available at http://lisanwanglab.org/DASHR.