OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels

Bunt, Jens, Hasselt, Nancy A., Zwijnenburg, Danny A., Koster, Jan, Versteeg, Rogier and Kool, Marcel (2013) OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels. Acta Neuropathologica, 125 3: 385-394. doi:10.1007/s00401-012-1069-2


Author Bunt, Jens
Hasselt, Nancy A.
Zwijnenburg, Danny A.
Koster, Jan
Versteeg, Rogier
Kool, Marcel
Title OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels
Journal name Acta Neuropathologica   Check publisher's open access policy
ISSN 0001-6322
1432-0533
Publication date 2013
Year available 2013
Sub-type Article (original research)
DOI 10.1007/s00401-012-1069-2
Volume 125
Issue 3
Start page 385
End page 394
Total pages 10
Place of publication Heidelberg, Germany
Publisher Springer
Collection year 2014
Language eng
Subject 2728 Clinical Neurology
2734 Pathology and Forensic Medicine
2804 Cellular and Molecular Neuroscience
Abstract Recent studies showed frequent mutations in histone H3 lysine 27 (H3K27) demethylases in medulloblastomas of Group 3 and Group 4, suggesting a role for H3K27 methylation in these tumors. Indeed, trimethylated H3K27 (H3K27me3) levels were shown to be higher in Group 3 and 4 tumors compared to WNT and SHH medulloblastomas, also in tumors without detectable mutations in demethylases. Here, we report that polycomb genes, required for H3K27 methylation, are consistently upregulated in Group 3 and 4 tumors. These tumors show high expression of the homeobox transcription factor OTX2. Silencing of OTX2 in D425 medulloblastoma cells resulted in downregulation of polycomb genes such as EZH2, EED, SUZ12 and RBBP4 and upregulation of H3K27 demethylases KDM6A, KDM6B, JARID2 and KDM7A. This was accompanied by decreased H3K27me3 and increased H3K27me1 levels in promoter regions. Strikingly, the decrease of H3K27me3 was most prominent in promoters that bind OTX2. OTX2-bound promoters showed high levels of the H3K4me3 and H3K9ac activation marks and intermediate levels of the H3K27me3 inactivation mark, reminiscent of a bivalent modification. After silencing of OTX2, H3K27me3 levels strongly dropped, but H3K4me3 and H3K9ac levels remained high. OTX2-bound bivalent genes showed high expression levels in D425, but the expression of most of these genes did not change after OTX2 silencing and loss of the H3K27me3 mark. Maintaining promoters in a bivalent state by sustaining H3K27 trimethylation therefore seems to be an important function of OTX2 in medulloblastoma, while other transcription factors might regulate the actual expression levels of these genes.
Keyword Chromatin immunoprecipitation
H3K27me3
Histone modification
Medulloblastoma
OTX2
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Queensland Brain Institute Publications
 
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Created: Sun, 23 Feb 2014, 15:53:40 EST by Jens Bunt on behalf of Queensland Brain Institute