The Histone Demethylases JMJD1A and JMJD2B Are Transcriptional Targets of Hypoxia-inducible Factor HIF

Abstract

Posttranslational histone modifications serve to store epigenetic information and control both nucleosome assembly and recruitment of non-histone proteins. Histone methylation occurs on arginine and lysine residues and is involved in the regulation of gene transcription. A dynamic control of these modifications is exerted by histone methyltransferases and the recently discovered histone demethylases. Here we show that the hypoxia-inducible factor HIF-1␣ binds to specific recognition sites in the genes encoding the jumonji family histone demethylases JMJD1A and JMJD2B and induces their expression. Accordingly, hypoxic cells express elevated levels of JMJD1A and JMJD2B mRNA and protein. Furthermore, we find increased expression of JMJD1A and JMJD2B in renal cancer cells that have lost the von Hippel Lindau tumor suppressor protein VHL and therefore display a deregulated expression of hypoxia-inducible factor. Studies on ectopically expressed JMJD1A and JMJD2B indicate that both proteins retain their histone lysine demethylase activity in hypoxia and thereby might impact the hypoxic gene expression program.

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…This transcription factor may influence gene expression at the level of histone modifications. Thus, HIF-1α binds to specific recognition sites in the genes encoding the jumonji family histone demethylases JMJD1A and JMJD2B and induces their expression in hypoxic conditions (Beyer et al, 2008). Genomic DNA methylation is also regulated by activation of HIF-1α through the up-regulation of methionine adenosyltransferase II alpha (MAT2a) in hepatoma cells under hypoxic conditions .…”

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

“…The histone demethylase KDM3A, shown to be HIF-1 induced in hypoxic cancer cells 26 was upregulated in primary rat cortical neurons upon DFO treatment and served as a positive control. However, neither SUV39H1 nor G9a mRNA expression was affected by DFO ( Figure 3).…”

Epigenetics: The epicenter of the hypoxic response

“…22 All of these Jumonji proteins are direct targets of HIF, and their expression is induced as a consequence of HIF binding during hypoxic exposure. [22][23][24][25] The relevance of increased levels of Jumonji proteins in hypoxic environments was further investigated by Beyer et al who acknowledged the importance of molecular oxygen for their demethylase activity and provided evidence that the demethylase activity of JMJD1A and JMJD2B was also increased in hypoxia, through studying H3K9me2 and H3K9me3 levels. 23 Finally, the importance of hypoxic regulation of histone demethylases has been highlighted by the fact that hypoxic induction of some genes, such as adrenomedullin, are dependent on JMJD1A-induced changes in histone methylation status at the gene promoter region.…”

“…In particular, these articles highlight the direct involvement of HIF-1α in the transactivation of Jumonji proteins within a hypoxic environment, both in vitro and in vivo. [22][23][24][25][26] Furthermore, protein and mRNA levels of JMJD1A (jumonji domain containing 1A) JMJD2B, JMJ2C and JARD1A are increased under hypoxic conditions in vitro (0.2-1%, up to 24 h) in a variety of cell lines. JMJD1A is also upregulated in several rat organs in vivo (8%, up to 12 h).…”