Journal
MOLECULAR CELL
Volume 80, Issue 5, Pages 915-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2020.10.024
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Funding
- Australian Department of Health Medical Frontiers Future Fund (MRFF) [MRF1175457]
- Australian National Health and Medical Research Council (NHMRC) [GNT1125645, GNT1138795, GNT1173711, GNT1173476, GNT1161832]
- Mater Foundation (Equity Trustees/AE Hingeley Trust)
- CSL Centenary Fellowship
- University of Queensland Genome Innovation Hub
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Transposable elements (TEs) drive genome evolution and are a notable source of pathogenesis, including cancer. While CpG methylation regulates TE activity, the locus-specific methylation landscape of mobile human TEs has to date proven largely inaccessible. Here, we apply new computational tools and long-read nanopore sequencing to directly infer CpG methylation of novel and extant TE insertions in hippocampus, heart, and liver, as well as paired tumor and non-tumor liver. As opposed to an indiscriminate stochastic process, we find pronounced demethylation of young long interspersed element 1 (LINE-1) retrotransposons in cancer, often distinct to the adjacent genome and other TEs. SINE-VNTR-Alu (SVA) retrotransposons, including their internal tandem repeat-associated CpG island, are near-universally methylated. We encounter allele-specific TE methylation and demethylation of aberrantly expressed young LINE-1s in normal tissues. Finally, we recover the complete sequences of tumor-specific LINE-1 insertions and their retrotransposition hallmarks, demonstrating how long-read sequencing can simultaneously survey the epigenome and detect somatic TE mobilization.
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