Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukaemia

Barrow, Timothy M, Wong Doo, Nicole, Milne, Roger L, Giles, Graham G, Willmore, Elaine, Strathdee, Gordon and Byun, Hyang-Min (2020) Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukaemia. Haematologica, 105. ISSN 1592-8721

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Abstract

Retrotransposons such as LINE-1 and Alu comprise >25% of the human genome. While global hypomethylation of these elements has been widely reported in solid tumours, their epigenetic dysregulation is yet to be characterised in chronic lymphocytic leukaemia, and there has been scant consideration of their evolutionary history that mediates sensitivity to hypomethylation. Here, we developed an approach for locus- and evolutionary subfamily-specific analysis of retrotransposons using the Illumina Infinium Human Methylation 450K microarray platform, which we applied to publicly-available datasets from chronic lymphocytic leukaemia and other haematological malignancies. We identified 9,797 microarray probes mapping to 117 LINE-1 subfamilies and 13,130 mapping to 37 Alu subfamilies. Of these, 10,782 were differentially methylated (PFDR<0.05) in chronic lymphocytic leukaemia patients (n=139) compared with healthy individuals (n=14), with enrichment at enhancers (p=0.002). Differential methylation was associated with evolutionary age of LINE-1 (r2=0.31, p=0.003) and Alu (r2=0.74, p=0.002) elements, with greater hypomethylation of older subfamilies (L1M, AluJ). Locus-specific hypomethylation was associated with differential expression of proximal genes, including DCLK2, HK1, ILRUN, TANK, TBCD, TNFRSF1B and TXNRD2, with higher expression of DCLK2 and TNFRSF1B associated with reduced patient survival. Hypomethylation at nine loci was highly frequent in chronic lymphocytic leukaemia (>90% patients) but not observed in healthy individuals or other leukaemias, and was detectable in blood samples taken prior to chronic lymphocytic leukaemia diagnosis in 9 of 82 individuals from the Melbourne Collaborative Cohort Study. Our results demonstrate differential methylation of retrotransposons in chronic lymphocytic leukaemia by their evolutionary heritage that modulates expression of proximal genes.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Sciences > Health Sciences
Divisions: Faculty of Health Sciences and Wellbeing
Depositing User: Timothy Barrow
Date Deposited: 10 Feb 2020 09:31
Last Modified: 02 Apr 2020 10:24
URI: http://sure.sunderland.ac.uk/id/eprint/11437
ORCID for Timothy M Barrow: ORCID iD orcid.org/0000-0003-4551-3857

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