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Cited by 195Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsRNA Research and Splicing

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Transposable Elements in TDP-43-Mediated Neurodegenerative Disorders

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Li, Wanhe, Jin, Ying, Prazak, Lisa, Hammell, Molly, Dubnau, Josh·2012·PLoS ONE
DOI 10.1371/journal.pone.0044099PMC PMC3434193
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Abstract

Elevated expression of specific transposable elements (TEs) has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.

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Figure 1 TDP-43 binds broadly to transposable element (TE)-derived transcripts. Magnitude (log2-fold) of enrichments (up) or depletions (down) are shown (A, rat; B, mouse) for significantly bound repeat elements grouped by class. MULTI method (see text) was used for A and B. (C) The majority of rat TE targets identified with MULTI also are identified (Left Panel, Rat) when analysis is restricted to reads that map uniquely (UNIQ) or when both uniquely mapped and multi-mapped reads that map to the same TE were included (UNIQ+SameEle). These conclusions also hold for TE targets whose binding is reduced in FTLD samples from human tissue relative to healthy controls (Left panel, Human). Most rat TE targets and differentially bound human TE targets identified from uniquely mapped reads are intergenic (Right panel). (D) For TDP-43, peaks (UNIQ+SameEle) over TE targets are tall and sharp with mean peak height of 158 counts/peak. In contrast, peak heights are lower for FUS (mean peak height of 17).
Figure 1 TDP-43 binds broadly to transposable element (TE)-derived transcripts. Magnitude (log2-fold) of enrichments (up) or depletions (down) are shown (A, rat; B, mouse) for significantly bound repeat elements grouped by class. MULTI method (see text) was used for A and B. (C) The majority of rat TE targets identified with MULTI also are identified (Left Panel, Rat) when analysis is restricted to reads that map uniquely (UNIQ) or when both uniquely mapped and multi-mapped reads that map to the same TE were included (UNIQ+SameEle). These conclusions also hold for TE targets whose binding is reduced in FTLD samples from human tissue relative to healthy controls (Left panel, Human). Most rat TE targets and differentially bound human TE targets identified from uniquely mapped reads are intergenic (Right panel). (D) For TDP-43, peaks (UNIQ+SameEle) over TE targets are tall and sharp with mean peak height of 158 counts/peak. In contrast, peak heights are lower for FUS (mean peak height of 17).CC BY · PubMed Central
Figure 2 TDP-43 binding to TEs is selectively lost in FTLD patients. (A) In the human CLIP-seq data from FTLD versus healthy control, 38 repeat elements showed significant (p-value< = 1e-5 and fold changes> = 2) differential binding. Log2 fold binding differences are shown for significantly enriched/depleted elements. (B,C,D) Peaks are shown in genome browser for one RefGene control (B) and two differentially targeted TEs (C,D) in Healthy (top) versus FTLD (bottom). (E) Enrichment for the UGUGU motif relative to its prevalence in the genome is shown across a 51-nt window surrounding binding sites (−25 nt, 25 nt). Healthy samples (Blue) show similar enrichment for the UGUGU pentamer motif among RefGene (solid) and repeat (dashed) sequences (RefGene/repeat motif enrichment ratio ≈1.3). In contrast, motif enrichment in FTLD samples (Red) is significantly reduced among repeat (dashed) annotations relative to RefGene (solid; p-value< = 0.01; RefGene/repeat motif enrichment ratio ≈2.0).
Figure 2 TDP-43 binding to TEs is selectively lost in FTLD patients. (A) In the human CLIP-seq data from FTLD versus healthy control, 38 repeat elements showed significant (p-value< = 1e-5 and fold changes> = 2) differential binding. Log2 fold binding differences are shown for significantly enriched/depleted elements. (B,C,D) Peaks are shown in genome browser for one RefGene control (B) and two differentially targeted TEs (C,D) in Healthy (top) versus FTLD (bottom). (E) Enrichment for the UGUGU motif relative to its prevalence in the genome is shown across a 51-nt window surrounding binding sites (−25 nt, 25 nt). Healthy samples (Blue) show similar enrichment for the UGUGU pentamer motif among RefGene (solid) and repeat (dashed) sequences (RefGene/repeat motif enrichment ratio ≈1.3). In contrast, motif enrichment in FTLD samples (Red) is significantly reduced among repeat (dashed) annotations relative to RefGene (solid; p-value< = 0.01; RefGene/repeat motif enrichment ratio ≈2.0).CC BY · PubMed Central
Figure 3 Concordance between mis-regulated TE transcripts upon TDP-43 manipulation and TDP-43 bound TE transcripts. (A,B) Over-expression [20] of TDP-43 in transgenic mice and depletion [19] of TDP-43 in mouse striatum each result in elevated expression of many TE derived transcripts. The majority of over-expressed TEs also were detected (Table S3) as binding targets by CLIP-seq (RED). A few showed elevated expression but were not detected as binding targets (BLUE).
Figure 3 Concordance between mis-regulated TE transcripts upon TDP-43 manipulation and TDP-43 bound TE transcripts. (A,B) Over-expression [20] of TDP-43 in transgenic mice and depletion [19] of TDP-43 in mouse striatum each result in elevated expression of many TE derived transcripts. The majority of over-expressed TEs also were detected (Table S3) as binding targets by CLIP-seq (RED). A few showed elevated expression but were not detected as binding targets (BLUE).CC BY · PubMed Central

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Metadata

Authors
Li, W., Jin, Y., Prazak, L., Hammell, M., & Dubnau, J.
Affiliations
Cold Spring Harbor Laboratory (US)
Corresponding author
  • Hammell, Molly
  • Dubnau, Josh
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-09-05
Volume
7
Issue
9
Pages
e44099
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0044099
PMC
PMC3434193
OpenAlex
W2023453519
Cited by
195
References
41
Citations by year
2026: 7 · 2025: 12 · 2024: 15 · 2023: 13 · 2022: 22 · 2021: 22 · 2020: 23 · 2019: 20 · 2018: 18 · 2017: 16 · 2016: 6 · 2015: 8 · 2014: 10 · 2013: 3
FWCI
4.39
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (TR01 5R01NS067690-03, R01NS067690)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
transposable elements, TDP-43, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, neurodegenerative diseases, RNA-protein interactions, gene expression dysregulation, RNA-binding proteins
MeSH terms
Animals, DNA Transposable Elements, DNA-Binding Proteins, Frontal Lobe, Humans, Molecular Sequence Data, Neurons, Protein Binding, RNA, Models, Statistical, Case-Control Studies, Genome, Neurodegenerative Diseases, Gene Expression Profiling, Mice, Rats

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