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Lookup NU author(s): Dr Timothy Barrow, Dr Elaine WillmoreORCiD, Dr Gordon Strathdee, Dr Hyang-Min ByunORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Retrotransposons such as LINE-1 and Alu comprise >25% of the human genome.While global hypomethylation of these elements has been widely reported in solidtumours, their epigenetic dysregulation is yet to be characterised in chroniclymphocytic leukaemia, and there has been scant consideration of their evolutionaryhistory that mediates sensitivity to hypomethylation. Here, we developed anapproach for locus- and evolutionary subfamily-specific analysis of retrotransposonsusing the Illumina Infinium Human Methylation 450K microarray platform, which weapplied to publicly-available datasets from chronic lymphocytic leukaemia and otherhaematological malignancies. We identified 9,797 microarray probes mapping to 117LINE-1 subfamilies and 13,130 mapping to 37 Alu subfamilies. Of these, 10,782were 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 greaterhypomethylation of older subfamilies (L1M, AluJ). Locus-specific hypomethylationwas associated with differential expression of proximal genes, including DCLK2,HK1, ILRUN, TANK, TBCD, TNFRSF1B and TXNRD2, with higher expression ofDCLK2 and TNFRSF1B associated with reduced patient survival. Hypomethylationat nine loci was highly frequent in chronic lymphocytic leukaemia (>90% patients) butnot observed in healthy individuals or other leukaemias, and was detectable in bloodsamples taken prior to chronic lymphocytic leukaemia diagnosis in 9 of 82 individualsfrom the Melbourne Collaborative Cohort Study. Our results demonstrate differentialmethylation of retrotransposons in chronic lymphocytic leukaemia by theirevolutionary heritage that modulates expression of proximal genes.
Author(s): Barrow TM, Wong Doo N, Milne RL, Giles GG, Willmore E, Strathdee G, Byun HM
Publication type: Article
Publication status: Published
Journal: Haematologica
Year: 2021
Volume: 106
Issue: 1
Pages: 98-110
Print publication date: 01/01/2021
Online publication date: 09/01/2020
Acceptance date: 27/12/2019
Date deposited: 30/10/2020
ISSN (print): 0390-6078
ISSN (electronic): 1592-8721
Publisher: Fondazione Ferrata Stori
URL: https://doi.org/10.3324/haematol.2019.228478
DOI: 10.3324/haematol.2019.228478
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