Transcriptional control in normoxia and hypoxia. (A) In normoxia, proteasomal degradation of HIFs prevents HIF-α binding to a hypoxia response element (HRE) and transcriptional activation does not occur. (B) The expression of other genes can be regulated by methylation at histones H3K9 and H3K27 by G9a and EZH2 respectively to maintain homeostasis. (C-E) In hypoxia, gene expression is regulated at multiple layers; (C) HIF-α is stabilised in hypoxia and is able to bind to HREs and activate transcription. (D) The transcriptional activity of HIF-α can be modulated by co-regulators; G9a methylates chromatin remodelling complex proteins such as Reptin and Pontin in hypoxia. Methylated Reptin negatively regulates transcriptional activation by HIF-α at a subset of HIF-α target genes by recruiting a transcriptional co-repressor. Conversely, Pontin methylation potentiates HIF-α-mediated transcription at another distinct subset of HIF-α target promoters by enhancing the recruitment of a transcriptional co-activator. (E) The expression of histone methyltransferases such as G9a and EZH2 is elevated in hypoxia which leads to silencing of tumour suppressors through the hypermethylation of histones H3K9 and H3K27.