Cargando…

Recurrent epimutations activate gene body promoters in primary glioblastoma

Aberrant DNA hypomethylation may play an important role in the growth rate of glioblastoma (GBM), but the functional impact on transcription remains poorly understood. We assayed the GBM methylome with MeDIP-seq and MRE-seq, adjusting for copy number differences, in a small set of non-glioma CpG isl...

Descripción completa

Detalles Bibliográficos
Autores principales: Nagarajan, Raman P., Zhang, Bo, Bell, Robert J.A., Johnson, Brett E., Olshen, Adam B., Sundaram, Vasavi, Li, Daofeng, Graham, Ashley E., Diaz, Aaron, Fouse, Shaun D., Smirnov, Ivan, Song, Jun, Paris, Pamela L., Wang, Ting, Costello, Joseph F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009606/
https://www.ncbi.nlm.nih.gov/pubmed/24709822
http://dx.doi.org/10.1101/gr.164707.113
_version_ 1782479778392047616
author Nagarajan, Raman P.
Zhang, Bo
Bell, Robert J.A.
Johnson, Brett E.
Olshen, Adam B.
Sundaram, Vasavi
Li, Daofeng
Graham, Ashley E.
Diaz, Aaron
Fouse, Shaun D.
Smirnov, Ivan
Song, Jun
Paris, Pamela L.
Wang, Ting
Costello, Joseph F.
author_facet Nagarajan, Raman P.
Zhang, Bo
Bell, Robert J.A.
Johnson, Brett E.
Olshen, Adam B.
Sundaram, Vasavi
Li, Daofeng
Graham, Ashley E.
Diaz, Aaron
Fouse, Shaun D.
Smirnov, Ivan
Song, Jun
Paris, Pamela L.
Wang, Ting
Costello, Joseph F.
author_sort Nagarajan, Raman P.
collection PubMed
description Aberrant DNA hypomethylation may play an important role in the growth rate of glioblastoma (GBM), but the functional impact on transcription remains poorly understood. We assayed the GBM methylome with MeDIP-seq and MRE-seq, adjusting for copy number differences, in a small set of non-glioma CpG island methylator phenotype (non-G-CIMP) primary tumors. Recurrent hypomethylated loci were enriched within a region of chromosome 5p15 that is specified as a cancer amplicon and also encompasses TERT, encoding telomerase reverse transcriptase, which plays a critical role in tumorigenesis. Overall, 76 gene body promoters were recurrently hypomethylated, including TERT and the oncogenes GLI3 and TP73. Recurring hypomethylation also affected previously unannotated alternative promoters, and luciferase reporter assays for three of four of these promoters confirmed strong promoter activity in GBM cells. Histone H3 lysine 4 trimethylation (H3K4me3) ChIP-seq on tissue from the GBMs uncovered peaks that coincide precisely with tumor-specific decrease of DNA methylation at 200 loci, 133 of which are in gene bodies. Detailed investigation of TP73 and TERT gene body hypomethylation demonstrated increased expression of corresponding alternate transcripts, which in TP73 encodes a truncated p73 protein with oncogenic function and in TERT encodes a putative reverse transcriptase-null protein. Our findings suggest that recurring gene body promoter hypomethylation events, along with histone H3K4 trimethylation, alter the transcriptional landscape of GBM through the activation of a limited number of normally silenced promoters within gene bodies, in at least one case leading to expression of an oncogenic protein.
format Online
Article
Text
id pubmed-4009606
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-40096062014-11-01 Recurrent epimutations activate gene body promoters in primary glioblastoma Nagarajan, Raman P. Zhang, Bo Bell, Robert J.A. Johnson, Brett E. Olshen, Adam B. Sundaram, Vasavi Li, Daofeng Graham, Ashley E. Diaz, Aaron Fouse, Shaun D. Smirnov, Ivan Song, Jun Paris, Pamela L. Wang, Ting Costello, Joseph F. Genome Res Research Aberrant DNA hypomethylation may play an important role in the growth rate of glioblastoma (GBM), but the functional impact on transcription remains poorly understood. We assayed the GBM methylome with MeDIP-seq and MRE-seq, adjusting for copy number differences, in a small set of non-glioma CpG island methylator phenotype (non-G-CIMP) primary tumors. Recurrent hypomethylated loci were enriched within a region of chromosome 5p15 that is specified as a cancer amplicon and also encompasses TERT, encoding telomerase reverse transcriptase, which plays a critical role in tumorigenesis. Overall, 76 gene body promoters were recurrently hypomethylated, including TERT and the oncogenes GLI3 and TP73. Recurring hypomethylation also affected previously unannotated alternative promoters, and luciferase reporter assays for three of four of these promoters confirmed strong promoter activity in GBM cells. Histone H3 lysine 4 trimethylation (H3K4me3) ChIP-seq on tissue from the GBMs uncovered peaks that coincide precisely with tumor-specific decrease of DNA methylation at 200 loci, 133 of which are in gene bodies. Detailed investigation of TP73 and TERT gene body hypomethylation demonstrated increased expression of corresponding alternate transcripts, which in TP73 encodes a truncated p73 protein with oncogenic function and in TERT encodes a putative reverse transcriptase-null protein. Our findings suggest that recurring gene body promoter hypomethylation events, along with histone H3K4 trimethylation, alter the transcriptional landscape of GBM through the activation of a limited number of normally silenced promoters within gene bodies, in at least one case leading to expression of an oncogenic protein. Cold Spring Harbor Laboratory Press 2014-05 /pmc/articles/PMC4009606/ /pubmed/24709822 http://dx.doi.org/10.1101/gr.164707.113 Text en © 2014 Nagarajan et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Nagarajan, Raman P.
Zhang, Bo
Bell, Robert J.A.
Johnson, Brett E.
Olshen, Adam B.
Sundaram, Vasavi
Li, Daofeng
Graham, Ashley E.
Diaz, Aaron
Fouse, Shaun D.
Smirnov, Ivan
Song, Jun
Paris, Pamela L.
Wang, Ting
Costello, Joseph F.
Recurrent epimutations activate gene body promoters in primary glioblastoma
title Recurrent epimutations activate gene body promoters in primary glioblastoma
title_full Recurrent epimutations activate gene body promoters in primary glioblastoma
title_fullStr Recurrent epimutations activate gene body promoters in primary glioblastoma
title_full_unstemmed Recurrent epimutations activate gene body promoters in primary glioblastoma
title_short Recurrent epimutations activate gene body promoters in primary glioblastoma
title_sort recurrent epimutations activate gene body promoters in primary glioblastoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009606/
https://www.ncbi.nlm.nih.gov/pubmed/24709822
http://dx.doi.org/10.1101/gr.164707.113
work_keys_str_mv AT nagarajanramanp recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT zhangbo recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT bellrobertja recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT johnsonbrette recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT olshenadamb recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT sundaramvasavi recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT lidaofeng recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT grahamashleye recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT diazaaron recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT fouseshaund recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT smirnovivan recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT songjun recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT parispamelal recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT wangting recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma
AT costellojosephf recurrentepimutationsactivategenebodypromotersinprimaryglioblastoma