Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 08 2023
01 08 2023
Historique:
received:
08
11
2022
revised:
30
03
2023
accepted:
25
05
2023
pmc-release:
01
02
2024
medline:
23
10
2023
pubmed:
30
5
2023
entrez:
30
5
2023
Statut:
ppublish
Résumé
Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. RNA sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses [long terminal repeats (LTR)]. Most differentially methylated regions (DMR) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in The Cancer Genome Atlas datasets of breast, colon, and prostate cancer. Overall, these findings indicate that TEs, specifically endogenous retroviruses, are demethylated and transcribed during transformation. Analysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.
Identifiants
pubmed: 37249603
pii: 727006
doi: 10.1158/0008-5472.CAN-22-3485
pmc: PMC10527578
mid: NIHMS1906354
doi:
Substances chimiques
DNA Transposable Elements
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2584-2599Subventions
Organisme : NCI NIH HHS
ID : R37 CA251270
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM130680
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA227259
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG066101
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA247756
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES011858
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA204592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA260691
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007748
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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