Sequence features of retrotransposons allow for epigenetic variability
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, United States
- Irell and Manella Graduate School of Biological Sciences, City of Hope, United States
- Van Andel Research Institute, United States
Figures
Figure 1 with 8 supplements
Sequence and chromatin context influence the establishment of a VM-IAPLTRs.
(A) All IAPLTR1 elements larger than 300 bps and the first 150bps of IAPEz-ints flanked by IAPLTR1 or IAPLTRs were clustered by sequence using PhyML with default settings. Major sequence variants …
Figure 1—figure supplement 1
Multiple sequence alignment of IAPLTR1s, IAPLTR2, and the first 150bps of IAPEz-int flanked by IAPLTR1/2 aligned by MAFFT with default settings (Katoh and Standley, 2013).
Bases present in less than 10 % of IAPLTR elements were trimmed from the alignment. Sequences were clustered using PhyML with default settings. Each base is visualized by a different color: thymine …
Figure 1—figure supplement 2
Consensus sequence of the IAPLTR1 clades identified in Figure 1—figure supplement 1.
Bases present in less than 10 % of IAPLTR elements were trimmed from the alignment. CpG dinucleotides are highlighted in light gray.
Figure 1—figure supplement 3
Gm21082 and KAP1 ChIP-seq signal mapped across all IAPLTR1 elements.
Consensus sequence of the IAPLTR1 clades at the region of increased ZFP989/Gm21082 binding. Arrows indicate locations of indels between clades. Previously identified Gm21082 binding motif from Wolf …
Figure 1—figure supplement 4
ZFP429, ZFP989, and KAP1 ChIP-seq signal mapped across all IAPLTR2 elements.
Figure 1—figure supplement 5
Association of IAPLTR2 and IAPEz-int clades for all IAPLTR2s and VM-IAPLTR2.
Figure 1—figure supplement 6
The percent of VM-IAPLTR1s clade three elements and non VM-IAPLTR1 clade three elements proximal to a constitutively expressed genes.
Each point refers to the percentage of IAPLTR1 proximal to a constitutively expressed gene at a given value. Distances were sampled every 2500bps.
Figure 1—figure supplement 7
Conservation of IAPLTR1 and IAPEz-int variants across mouse strains.
Presence or absence of a IAP was determined using structural variants identified from the Sanger mouse genome project. If the entire IAP was found to be missing from the other mouse assembly, the …
Figure 1—figure supplement 8
Model of IAPLTR and IAPEz-int interactions the height of each IAPEz-int refers to the percentage of IAP elements.
Figure 2 with 4 supplements
Divergent VM-IAPs elements have high CpG density and recruitment of ZF-CxxC proteins.
(A) Percent of ERV LTRs elements that are variably methylated for a given TE subfamily and average maximum CpG score of the TE subfamily. The size of each dot is determined by the number of VM-loci …
Figure 2—figure supplement 1
TET1 ChIP-seq signal mapped across all IAPLTR1 elements.
Figure 2—figure supplement 2
CFP1 profiling at IAPLTRs.
(A) Aggregate plots of Cfp1 signal at variably methylated and other IAPLTRs. Heatmaps of Cfp1 signal at (B) VM-IAPLTRs and (C) all other IAPLTR1 and IAPLTR2 elements (2819 elements). Reads were …
Figure 2—figure supplement 3
Enrichment of H3K4me3 at VM-IAPLTRs.
(A) Observed over expected H3K4me3 signal at variably methylated and non-variably methylated IAPLTRs. Expected H3K4me3 signal determined using average H3K4me3 signal at 50 randomly selected loci …
Figure 2—figure supplement 4
MEME identified motifs present in VM-IAPLTRs that contain CFP1-binding sites.
P-values obtained from MEME.
Figure 3 with 1 supplement
Variably methylated loci in humans are enriched for evolutionarily recent CpG-dense TEs.
(A) Observed over expected distribution of VM-TE elements in humans stratified by the evolutionary age of the TE. Expected distribution was determined using a random sampling of the hg38 genome the …
Figure 3—figure supplement 1
Scatter plot showing the percent of SINEs and LINEs that display variable methylation for a given TE subfamily and average CpG score of the TE subfamily in humans.
Figure 4 with 2 supplements
CpG dense TEs are hypomethylated and recruit ZF-CxxC proteins in the absence of KZFP-mediated silencing.
(A) UCSC genome browser screenshot of an LTR12C element which is hypomethylated in Tc1 mice and shows novel CFP1 recruitment in Tc1 mice. (B) CpG methylation of TE CpG islands (CGIs) and other TEs …
Figure 4—figure supplement 1
CpG methylation of all TEs on human chromosome 21.
TEs were separated by CpG density and their capability of being silenced by a KZFP element shared between mouse and humans. Largely, these silenced repeat CGIs were found at Alu elements.
Figure 4—figure supplement 2
CFP1 signal at all non-repeat derived CpG islands on human chromosome 21 in Tc1 mice and humans.
Figure 5 with 2 supplements
Trim28 haploinsufficiency leads to activation of evolutionarily recent and CpG dense TEs.
(A) Genome screenshot of an IAPLTR2 element with novel H3K4me3 enrichment in Trim28 haploinsufficient mice. (B) Breakdown of loci with novel H3K4me3 in Trim28 haploinsufficient mice. Age of each TE …
Figure 5—figure supplement 1
Heatmap and aggregate plots of H3K4me3 and CFP1 signal at loci with novel H3K4me3 signal in Trim28 D9/+ mice.
Figure 5—figure supplement 2
Evolutionary age of all TEs in the mm10 genome.
Evolutionary age was obtained from Dfam (Hubley et al., 2016).
Figure 6 with 1 supplement
Model for variable methylated transposable elements.
Loci with high CpG density and loss of KZFP binding have the potential to recruit ZF-CxxC proteins to protect these TEs from being silenced. However, elements with high CpG density but strong KZFP …
Figure 6—figure supplement 1
Comparison of the IAPLTR1 associated with the ‘master’ IAP element identified in the C3H mice compared to the consensus sequence for each clade.
Only a portion of the IAPLTR1 containing identifiable sequence variants for each clade is shown to improve visibility.
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Strain, strain background (Mus musculus) | Trim29+/D9 | Blewitt et al., 2005 | (RRID:MGI:3821610) | Haploinsufficient for Trim28 |
| Strain, strain background (Mus musculus) | B6129S-Tc(HSA21)1TybEmcf/J | The Jackson Laboratory | Stock No: 010801 (JAX)(RRID:IMSR_JAX:010801) | 2 Mb of a freely segregating human fragment of Chr21 |
| Antibody | Rabbit Polyclonal anti-CFP1 antibody | Millipore | ABE211(RRID:AB_10806210) | CUT&RUN(1:50 dilution) |
| Antibody | Rabbit polyclonal anti-H3K4me3Antibody | Abcam | ab8580(RRID:AB_306649) | ChIP-seq(2 µg antibody per25 µg chromatin) |
Additional files
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Transparent reporting form
- https://cdn.elifesciences.org/articles/71104/elife-71104-transrepform1-v3.docx
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Supplementary file 1
Annotation of IAP clades.
- https://cdn.elifesciences.org/articles/71104/elife-71104-supp1-v3.xlsx
