Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls WT1 expression in myeloid leukemia cells

Gregory McCarty, David M. Loeb

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

WT1 is a transcription factor expressed in hematopoietic stem cells and in most cases of myeloid leukemia. We investigated the roles of hypoxia and epigenetics in the regulation of WT1 expression in myeloid leukemia cells. WT1 expression correlates with hypomethylation of the CpG island in Intron 1, and pharmacologic demethylation of this CpG island induces WT1 mRNA expression. Hypoxia causes decreases in DNMT expression and activity and increased expression and activity of TET2 and TET3, resulting in demethylation of this CpG island and expression of WT1 mRNA. Demethylation of the CpG island, either from pharmacologic treatment or induction of hypoxia, results in transcription of an anti-sense-oriented lncRNA, and inhibiting lncRNA expression with shRNA blocks WT1 mRNA expression. These results reveal a novel model of hypoxia-mediated epigenetic gene regulation. In addition, this is the first report that TET2 and TET3, increasingly recognized as important epigenetic regulators of gene expression in stem cells and in cancer cells, can be regulated by hypoxia, providing a solid mechanistic link between hypoxia and epigenetic regulation of gene expression with important implications for the role of hypoxia in stem cell function.

Original languageEnglish (US)
Article numbere0119837
JournalPLoS One
Volume10
Issue number3
DOIs
StatePublished - Mar 20 2015
Externally publishedYes

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Long Noncoding RNA
myeloid leukemia
CpG Islands
Myeloid Leukemia
Myeloid Cells
Epigenomics
epigenetics
hypoxia
Stem cells
Gene expression
Messenger RNA
cells
Transcription
stem cells
Introns
Small Interfering RNA
Transcription Factors
Cells
Neoplastic Stem Cells
gene expression regulation

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls WT1 expression in myeloid leukemia cells. / McCarty, Gregory; Loeb, David M.

In: PLoS One, Vol. 10, No. 3, e0119837, 20.03.2015.

Research output: Contribution to journalArticle

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