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Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.

Publication ,  Journal Article
Wortham, M; Guo, C; Zhang, M; Song, L; Lee, B-K; Iyer, VR; Furey, TS; Crawford, GE; Yan, H; He, Y
Published in: PLoS One
2014

Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2014

Volume

9

Issue

9

Start / End Page

e107156

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Trans-Activators
  • Retinoids
  • Regulatory Elements, Transcriptional
  • Promoter Regions, Genetic
  • Otx Transcription Factors
  • Medulloblastoma
  • Humans
  • General Science & Technology
  • Gene Expression Regulation, Neoplastic
 

Citation

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Wortham, M., Guo, C., Zhang, M., Song, L., Lee, B.-K., Iyer, V. R., … He, Y. (2014). Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma. PLoS One, 9(9), e107156. https://doi.org/10.1371/journal.pone.0107156
Wortham, Matthew, Changcun Guo, Monica Zhang, Lingyun Song, Bum-Kyu Lee, Vishwanath R. Iyer, Terrence S. Furey, Gregory E. Crawford, Hai Yan, and Yiping He. “Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.PLoS One 9, no. 9 (2014): e107156. https://doi.org/10.1371/journal.pone.0107156.
Wortham, Matthew, et al. “Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.PLoS One, vol. 9, no. 9, 2014, p. e107156. Pubmed, doi:10.1371/journal.pone.0107156.
Wortham M, Guo C, Zhang M, Song L, Lee B-K, Iyer VR, Furey TS, Crawford GE, Yan H, He Y. Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma. PLoS One. 2014;9(9):e107156.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2014

Volume

9

Issue

9

Start / End Page

e107156

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Trans-Activators
  • Retinoids
  • Regulatory Elements, Transcriptional
  • Promoter Regions, Genetic
  • Otx Transcription Factors
  • Medulloblastoma
  • Humans
  • General Science & Technology
  • Gene Expression Regulation, Neoplastic