DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma

Lynda B. Bennett, Jennifer L. Schnabel, Jean M. Kelchen, Kristen H. Taylor, Juyuan Guo, Gerald L. Arthur, Christos N. Papageorgio, Huidong Shi, Charles W. Caldwell

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

High-throughput microarray technologies were used to study DNA methylation accompanied by transcriptional changes in follicular lymphoma (FL). Using Methylated CpG Island Amplification with Microarrays to study CpG Island DNA methylation in FL, we discovered widespread hypermethylation of homeobox genes and previously identified targets of polycomb repressive complex 2 (PRC2) in cell lines and primary tumors, but not in benign follicular hyperplasia (BFH). DNA methylation for HOXA11, HOXD10, HOXB7, HOXC12, PAX6, LHX9, SFMBT2, EN2, and PAX7 was independently validated in the RL cell line and HOXA11, HOXD10, PAX6, and EN2 in primary tumors. Combined Bisulfite Restriction Analysis (COBRA) also established DNA methylation for the previously identified PRC2 targets DCC, DES, GAD2, AQP5, GPR61, GRIA4, GJD2, and AMPH in FL but not in BFH. Gene expression analyses revealed 411 genes that were hypermethylated and transcriptionally repressed in RL, 74% of which were reactivated by the demethylating agent 5-aza-2′-deoxycytidine (5-azaD) plus or minus the histone deacetylase inhibitor trichostatin A (TSA). Forty genes were also downregulated in primary FL. Our results suggest that extensive hypermethylation in promoters of polycomb target genes is a characteristic of FL and that loss of expression of certain SUZ12 target genes could be functionally relevant for lymphomagenesis.

Original languageEnglish (US)
Pages (from-to)828-841
Number of pages14
JournalGenes Chromosomes and Cancer
Volume48
Issue number9
DOIs
StatePublished - Sep 1 2009

Fingerprint

Follicular Lymphoma
DNA Methylation
Polycomb Repressive Complex 2
DNA
CpG Islands
decitabine
Genes
Hyperplasia
trichostatin A
Histone Deacetylase Inhibitors
Homeobox Genes
Tumor Cell Line
Down-Regulation
Technology
Gene Expression
Cell Line
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Bennett, L. B., Schnabel, J. L., Kelchen, J. M., Taylor, K. H., Guo, J., Arthur, G. L., ... Caldwell, C. W. (2009). DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma. Genes Chromosomes and Cancer, 48(9), 828-841. https://doi.org/10.1002/gcc.20687

DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma. / Bennett, Lynda B.; Schnabel, Jennifer L.; Kelchen, Jean M.; Taylor, Kristen H.; Guo, Juyuan; Arthur, Gerald L.; Papageorgio, Christos N.; Shi, Huidong; Caldwell, Charles W.

In: Genes Chromosomes and Cancer, Vol. 48, No. 9, 01.09.2009, p. 828-841.

Research output: Contribution to journalArticle

Bennett, LB, Schnabel, JL, Kelchen, JM, Taylor, KH, Guo, J, Arthur, GL, Papageorgio, CN, Shi, H & Caldwell, CW 2009, 'DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma', Genes Chromosomes and Cancer, vol. 48, no. 9, pp. 828-841. https://doi.org/10.1002/gcc.20687
Bennett LB, Schnabel JL, Kelchen JM, Taylor KH, Guo J, Arthur GL et al. DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma. Genes Chromosomes and Cancer. 2009 Sep 1;48(9):828-841. https://doi.org/10.1002/gcc.20687
Bennett, Lynda B. ; Schnabel, Jennifer L. ; Kelchen, Jean M. ; Taylor, Kristen H. ; Guo, Juyuan ; Arthur, Gerald L. ; Papageorgio, Christos N. ; Shi, Huidong ; Caldwell, Charles W. / DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma. In: Genes Chromosomes and Cancer. 2009 ; Vol. 48, No. 9. pp. 828-841.
@article{4869bdae3b69441a83e31cc132582887,
title = "DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma",
abstract = "High-throughput microarray technologies were used to study DNA methylation accompanied by transcriptional changes in follicular lymphoma (FL). Using Methylated CpG Island Amplification with Microarrays to study CpG Island DNA methylation in FL, we discovered widespread hypermethylation of homeobox genes and previously identified targets of polycomb repressive complex 2 (PRC2) in cell lines and primary tumors, but not in benign follicular hyperplasia (BFH). DNA methylation for HOXA11, HOXD10, HOXB7, HOXC12, PAX6, LHX9, SFMBT2, EN2, and PAX7 was independently validated in the RL cell line and HOXA11, HOXD10, PAX6, and EN2 in primary tumors. Combined Bisulfite Restriction Analysis (COBRA) also established DNA methylation for the previously identified PRC2 targets DCC, DES, GAD2, AQP5, GPR61, GRIA4, GJD2, and AMPH in FL but not in BFH. Gene expression analyses revealed 411 genes that were hypermethylated and transcriptionally repressed in RL, 74{\%} of which were reactivated by the demethylating agent 5-aza-2′-deoxycytidine (5-azaD) plus or minus the histone deacetylase inhibitor trichostatin A (TSA). Forty genes were also downregulated in primary FL. Our results suggest that extensive hypermethylation in promoters of polycomb target genes is a characteristic of FL and that loss of expression of certain SUZ12 target genes could be functionally relevant for lymphomagenesis.",
author = "Bennett, {Lynda B.} and Schnabel, {Jennifer L.} and Kelchen, {Jean M.} and Taylor, {Kristen H.} and Juyuan Guo and Arthur, {Gerald L.} and Papageorgio, {Christos N.} and Huidong Shi and Caldwell, {Charles W.}",
year = "2009",
month = "9",
day = "1",
doi = "10.1002/gcc.20687",
language = "English (US)",
volume = "48",
pages = "828--841",
journal = "Genes Chromosomes and Cancer",
issn = "1045-2257",
publisher = "Wiley-Liss Inc.",
number = "9",

}

TY - JOUR

T1 - DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma

AU - Bennett, Lynda B.

AU - Schnabel, Jennifer L.

AU - Kelchen, Jean M.

AU - Taylor, Kristen H.

AU - Guo, Juyuan

AU - Arthur, Gerald L.

AU - Papageorgio, Christos N.

AU - Shi, Huidong

AU - Caldwell, Charles W.

PY - 2009/9/1

Y1 - 2009/9/1

N2 - High-throughput microarray technologies were used to study DNA methylation accompanied by transcriptional changes in follicular lymphoma (FL). Using Methylated CpG Island Amplification with Microarrays to study CpG Island DNA methylation in FL, we discovered widespread hypermethylation of homeobox genes and previously identified targets of polycomb repressive complex 2 (PRC2) in cell lines and primary tumors, but not in benign follicular hyperplasia (BFH). DNA methylation for HOXA11, HOXD10, HOXB7, HOXC12, PAX6, LHX9, SFMBT2, EN2, and PAX7 was independently validated in the RL cell line and HOXA11, HOXD10, PAX6, and EN2 in primary tumors. Combined Bisulfite Restriction Analysis (COBRA) also established DNA methylation for the previously identified PRC2 targets DCC, DES, GAD2, AQP5, GPR61, GRIA4, GJD2, and AMPH in FL but not in BFH. Gene expression analyses revealed 411 genes that were hypermethylated and transcriptionally repressed in RL, 74% of which were reactivated by the demethylating agent 5-aza-2′-deoxycytidine (5-azaD) plus or minus the histone deacetylase inhibitor trichostatin A (TSA). Forty genes were also downregulated in primary FL. Our results suggest that extensive hypermethylation in promoters of polycomb target genes is a characteristic of FL and that loss of expression of certain SUZ12 target genes could be functionally relevant for lymphomagenesis.

AB - High-throughput microarray technologies were used to study DNA methylation accompanied by transcriptional changes in follicular lymphoma (FL). Using Methylated CpG Island Amplification with Microarrays to study CpG Island DNA methylation in FL, we discovered widespread hypermethylation of homeobox genes and previously identified targets of polycomb repressive complex 2 (PRC2) in cell lines and primary tumors, but not in benign follicular hyperplasia (BFH). DNA methylation for HOXA11, HOXD10, HOXB7, HOXC12, PAX6, LHX9, SFMBT2, EN2, and PAX7 was independently validated in the RL cell line and HOXA11, HOXD10, PAX6, and EN2 in primary tumors. Combined Bisulfite Restriction Analysis (COBRA) also established DNA methylation for the previously identified PRC2 targets DCC, DES, GAD2, AQP5, GPR61, GRIA4, GJD2, and AMPH in FL but not in BFH. Gene expression analyses revealed 411 genes that were hypermethylated and transcriptionally repressed in RL, 74% of which were reactivated by the demethylating agent 5-aza-2′-deoxycytidine (5-azaD) plus or minus the histone deacetylase inhibitor trichostatin A (TSA). Forty genes were also downregulated in primary FL. Our results suggest that extensive hypermethylation in promoters of polycomb target genes is a characteristic of FL and that loss of expression of certain SUZ12 target genes could be functionally relevant for lymphomagenesis.

UR - http://www.scopus.com/inward/record.url?scp=68549099896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68549099896&partnerID=8YFLogxK

U2 - 10.1002/gcc.20687

DO - 10.1002/gcc.20687

M3 - Article

VL - 48

SP - 828

EP - 841

JO - Genes Chromosomes and Cancer

JF - Genes Chromosomes and Cancer

SN - 1045-2257

IS - 9

ER -