Gene transcription and chromatin regulation in hypoxia

Abstract

Oxygen sensing is an essential feature of metazoan biology and reductions in oxygen availability (hypoxia) have both physiological and pathophysiological implications. Co-ordinated mechanisms have evolved for sensing and responding to hypoxia, which involve diverse biological outputs, with the main aim of restoring oxygen homeostasis. This includes a dynamic gene transcriptional response, the central drivers of which are the hypoxia-inducible factor (HIF) family of transcription factors. HIFs are regulated in an oxygen-dependent manner and while their role in hypoxia is well established, it is apparent that other key players are required for gene expression control in hypoxia. In this review, we highlight the current understanding of the known and potential molecular mechanisms underpinning gene transcriptional responses to hypoxia in mammals, with a focus on oxygen-dependent effects on chromatin structure.

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

“…As mentioned earlier HIFs are the master regulators of gene transcriptional changes in hypoxia and this has been extensively reviewed previously [ 2 , 11 , 203 ]. The discovery of hypoxia responsive genes and HIF targets has been driven greatly by transcript profiling and genome occupancy technologies, including microarrays, RNA-seq and ChIP-seq (reviewed in [ 15 , 16 , 204 ]). These analyses of publicly available transcriptional datasets [ 205 , 206 ] have shed light on cell type differences in hypoxia responsive genes and HIF targets on a genome wide scale, as well as identifying hypoxic signatures conserved across multiple cell types.…”

“…Why different cell types have different transcriptional responses to hypoxia and HIF target genes is an important question for the field, with chromatin structure organisation thought to be a major factor in conferring specificity. Further to HIF isoform expression and activity, evidence points towards pre-established chromatin accessibility and local chromatin environment, including RNA pol II availability, pre-existing promoter enhancer interactions at HREs, and HRE DNA methylation status, as cell-type specificity determinants of hypoxia transcriptional responses (reviewed in [ 15 , 16 , 204 , 207 ]).…”

“…Genetic models in several model organisms have helped identify the key roles of HIFs as well as 2-OGDs in development and disease ( Table 2 ; Supplementary Table S2 ). Furthermore, genome wide mapping techniques such as chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and Chromatin capture have more recently been used to better understand how cells responds to changes in oxygen, but also in response to 2-OGD inhibition ([ 13 , 14 ] and reviewed in [ 15 , 16 ]).…”

Roles Of HIF and 2-Oxoglutarate Dependent Enzymes in Controlling Gene Expression In Hypoxia

“…Some mRNAs contain an RNA HRE (rHRE), a sequence which can recruit an alternative initiation complex for selective cap-dependent translation [44]. This complex involves HIF-2α, one of [11][12][13]). However, this is still a vastly unexplored aspect of the hypoxia response.…”

“…There are now thousands of identified hypoxia responsive genes and over 100 validated HIF target genes, with over a thousand putative targets, and all classes of RNAs can be induced by low oxygen (reviewed in [11]). The discovery of hypoxia responsive genes and HIF targets has been driven greatly by transcript profiling and genome occupancy technologies, including microarrays, RNA-seq and ChIPseq (reviewed in [12][13][14]). These and analyses of publicly available transcriptional datasets [15,16] [12][13][14]17]).…”