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. 2018 Jun 18;19(1):468.
doi: 10.1186/s12864-018-4850-3.

Transposable elements generate regulatory novelty in a tissue-specific fashion

Marco Trizzino  1   2 , Aurélie Kapusta  3   4 , Christopher D Brown  5   6
Affiliations

Transposable elements generate regulatory novelty in a tissue-specific fashion

Marco Trizzino et al. BMC Genomics. .

Abstract

Background: Transposable elements (TE) are an important source of evolutionary novelty in gene regulation. However, the mechanisms by which TEs contribute to gene expression are largely uncharacterized.

Results: Here, we leverage Roadmap and GTEx data to investigate the association of TEs with active and repressed chromatin in 24 tissues. We find 112 human TE families enriched in active regions of the genome across tissues. Short Interspersed Nuclear Elements (SINEs) and DNA transposons are the most frequently enriched classes, while Long Terminal Repeat Retrotransposons (LTRs) are often enriched in a tissue-specific manner. We report across-tissue variability in TE enrichment in active regions. Genes with consistent expression across tissues are less likely to be associated with TE insertions. TE presence in repressed regions similarly follows tissue-specific patterns. Moreover, different TE classes correlate with different repressive marks: LTRs and Long Interspersed Nuclear Elements (LINEs) are overrepresented in regions marked by H3K9me3, while the other TEs are more likely to overlap regions with H3K27me3. Young TEs are typically enriched in repressed regions and depleted in active regions. We detect multiple instances of TEs that are enriched in tissue-specific active regulatory regions. Such TEs contain binding sites for transcription factors that are master regulators for the given tissue. These TEs are enriched in intronic enhancers, and their tissue-specific enrichment correlates with tissue-specific variations in the expression of the nearest genes.

Conclusions: We provide an integrated overview of the contribution of TEs to human gene regulation. Expanding previous analyses, we demonstrate that TEs can potentially contribute to the turnover of regulatory sequences in a tissue-specific fashion.

Keywords: Gene regulation; Tissue-specific; Transcription factors; Transposons.

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Figures

Fig. 1
Fig. 1
Transposable elements are enriched in active genomic regions. (a) The plot displays the numbers of enriched TE families in the active genomic regions for each tissue (FDR < 5%). The distribution suggests a tissue-specific pattern. (b) Stacked-bar charts show TE class composition for the TE families enriched in active regions (FDR < 5%). SINE and DNA transposons are the dominant TEs enriched in active regions. (c) The TEs enriched in active regions are depleted from promoters and intergenic regions, while they are significantly enriched in intronic regions
Fig. 2
Fig. 2
Transposable elements are enriched in repressed genomic regions. (a) The plot displays the numbers of enriched TE families in the repressed genomic regions for each tissue (FDR < 5%). The distribution suggests a tissue-specific pattern. (b) Stacked-chart plot shows class composition for the TE families enriched in repressed regions (FDR < 5%). (c) Across tissues, the repressed TEs overlap H3K27me3 more than expected by chance, while H3K9me3 is underrepresented. (d) Pie-charts show class composition for the TEs overlapping H3K27me3 and H3K9me3
Fig. 3
Fig. 3
Genes with higher expression variance are more tolerant towards TE insertion. Human genes were split into four categories: 1) Genes associated with TEs that are only found in active regions across tissues; 2) Genes associated with TEs that are found in active or repressed regions in a tissue-specific fashion; 3) Genes associated with TEs that are only found in repressed regions; 4) Genes never associated with TE insertions. The violin plots display the distribution of the GTEx gene expression variance, normalized by mean expression, for each of the four categories
Fig. 4
Fig. 4
Transposable elements have tissue-specific enrichment in active regions. The plot displays the distribution of the effect sizes (Z-scores from permutation test, see methods) for each TE enriched in active regions (FDR < 5%), in each tissue. The higher the Z-score, the more tissue-specific is the enrichment
Fig. 5
Fig. 5
Tissue-specific TEs are enriched for TF binding sites, are mostly intronic, and affect gene expression. (a) Motifs enriched in the regions overlapping X7C and and Charlie15a TEs in the breast. (b) Boxplot comparing mean expression for the genes associated to X7C and and Charlie15a in the breast vs all the other tissues. (c) Genomic distribution of the regions overlapping X7C and and Charlie15a TEs in the breast. (d) Motifs enriched in the regions overlapping LTR13_ TEs in pancreas and LCL cells. (e) Boxplot comparing mean expression for the genes associated to LTR13_ in the LCLs vs all the other tissues. (f) Genomic distribution of the regions overlapping LTR13_ in the LCLs. (g) Motifs enriched in the regions overlapping SVAs in the adipose nuclei. (h) Boxplot comparing mean expression for the genes associated to SVAs in the adipose nuclei vs all the other tissues. (i) Genomic distribution of the regions overlapping SVAs in the adipose nuclei. (j) Motifs enriched in the regions overlapping SVAs in the liver. (k) Boxplot comparing mean expression for the genes associated to SVAs in the liver vs all the other tissues. (l) Genomic distribution of the regions overlapping SVAs in the liver
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