title: Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls WT1 expression in myeloid leukemia cells.
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 antisense-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.
authors: Department of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States of America.
authors: Gregory
authors: G
authors: McCarty
authors: Department of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States of America.
authors: David M
authors: DM
authors: Loeb
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D056426:Genetic Loci; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007438:Introns; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000235:genetics*; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; D016372:RNA, Antisense; D062085:RNA, Long Noncoding; D025721:WT1 Proteins; C578792:TET3 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases