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DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma
Author(s) -
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.
Publication year - 2009
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20687
Subject(s) - dna methylation , demethylating agent , biology , trichostatin a , microbiology and biotechnology , cpg site , cancer research , epigenetics , bisulfite sequencing , methylation , histone deacetylase , histone , genetics , gene , gene expression
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. © 2009 Wiley‐Liss, Inc.