Abstract
In human, the 39 coding HOX genes and 18 referenced noncoding antisense transcripts are arranged in four genomic clusters named HOXA, B, C, and D. This highly conserved family belongs to the homeobox class of genes that encode transcription factors required for normal development. Therefore, HOX gene deregulation might contribute to the development of many cancer types. Here, we study HOX gene deregulation in adult glioma, a common type of primary brain tumor. We performed extensive molecular analysis of tumor samples, classified according to their isocitrate dehydrogenase (IDH1) gene mutation status, and of glioma stem cells. We found widespread expression of sense and antisense HOX transcripts only in aggressive (IDHwt) glioma samples, although the four HOX clusters displayed DNA hypermethylation. Integrative analysis of expression, DNA methylation, and histone modification signatures along the clusters revealed that HOX gene upregulation relies on canonical and alternative bivalent CpG island promoters that escape hypermethylation. H3K27me3 loss at these promoters emerges as the main cause of widespread HOX gene upregulation in IDHwt glioma cell lines and tumors. Our study provides the first comprehensive description of the epigenetic changes at HOX clusters and their contribution to the transcriptional changes observed in adult glioma. It also identified putative ‘master’ HOX proteins that might contribute to the tumorigenic potential of glioma stem cells.
Highlights
Glioma is the most frequent primary malignant brain tumor worldwide, with more than 200,000 cases per year
2-5 Chromatin analyses Chromatin immunoprecipitation-quantitative PCR (qPCR) of glioma samples Antibodies against histone H3 acetylated at lysine 9 (H3K9ac) (Millipore 06-942), H3K4me3 (Diagenode 03-050) and H3K27me3 (Millipore 07-449) were used to assess the enrichment of these histone marks at selected genes by chromatin immunoprecipitation (ChIP) of native chromatin isolated from frozen tissue samples (n=7 IDH2 are wild type (IDHwt) glioma, n=5 IDHmut glioma, n=5 control samples), as previously described [30]
We found that the binding sites of 13 transcription factors, including six HOX transcription factors, were enriched at 44 HOX transcripts expressed in IDHwt glioma samples (Fig. 3A)
Summary
Glioma is the most frequent primary malignant brain tumor worldwide, with more than 200,000 cases per year. In glioma and in GBM, many HOX factors are upregulated (transcript and protein level), suggesting that all four clusters are deregulated [14,15,16,17,18] These findings are based on studies performed using different tumor samples or cancer cell lines and different methods to assess the expression. We recently showed that HOX genes belong to a discrete class of genes characterized by ectopic expression, DNA hypermethylation, and H3K27me loss in IDHwt tumors [22]. These observations suggest that the mechanism underlying HOX gene deregulation in glioma is complex and that the main driving force remains to be determined. We carried out an extensive molecular analysis of IDHmut and IDHwt glioma samples and integrative molecular analyses in GSC lines
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