Regulation of chromatin accessibility by hypoxia and HIF

Abstract

Reduced oxygen availability (hypoxia) can act as a signalling cue in physiological processes such as development, but also in pathological conditions such as cancer or ischaemic disease. As such, understanding how cells and organisms respond to hypoxia is of great importance. The family of transcription factors called Hypoxia Inducible Factors (HIFs) coordinate a transcriptional programme required for survival and adaptation to hypoxia. The effects of HIF on chromatin accessibility landscape are still unclear. Here, using genome wide mapping of chromatin accessibility via ATAC-seq, we find hypoxia induces loci specific changes in chromatin accessibility are enriched at a subset hypoxia transcriptionally responsive genes, agreeing with previous data using other models. We show for the first time that hypoxia inducible changes in chromatin accessibility across the genome are predominantly HIF dependent, rapidly reversible upon reoxygenation and partially mimicked by HIF-α stabilisation independent of molecular dioxygenase inhibition. This work demonstrates that HIF is central to chromatin accessibility alterations in hypoxia, and has implications for our understanding of gene expression regulation by hypoxia and HIF.

Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation

“…3A) . As the HIF-1 transcription factor is known to regulate chromatin in hypoxic conditions, we further investigated the oxygen-dependency of DDX5 repression and possible HIF involvement, using a range of hypoxic conditions (<0.1 or 2% O 2 ) as well as the hypoxia mimetics CoCl 2 and DFO 32 . Exposure to 2% O 2 , CoCl 2 or DFO, had little or no effect on DDX5 expression, indicating that the repression of DDX5 is unlikely to be dependent on HIF-mediated signaling ( Fig.…”

“…Our ATACseq analysis suggests that in most cases the repression of the R-loop interactome correlates with decreased chromatin accessibility, likely leading to reduced transcription. Changes in chromatin accessibility in hypoxia have been previously characterized in hypoxia-induced cardiac damage, adaptation to high-altitude, or cancer cell lines, and both chromatin condensation and increased open chromatin at various loci, including hypoxia-responsive genes, were reported 32,36–38 . While changes to chromatin in hypoxia have been largely attributed to changes in chromatin modifying enzymes, it is also likely that changes in transcription factor activity in these conditions may impact chromatin and ultimately accessibility/gene expression 39 .…”

“…Our ATACseq analysis suggests that in the majority of cases the repression of the R-loop interactome correlates with decreased chromatin accessibility, likely leading to reduced transcription. Changes in chromatin accessibility in hypoxia have been previously characterized in hypoxia-induced cardiac damage, adaptation to high-altitude, or cancer cell lines, and both chromatin condensation and increased open chromatin at various loci, including hypoxia-responsive genes, were reported 38–41 . Recently, ATACseq was also used to demonstrate that the type I interferon pathway is downregulated in hypoxia, and that this is dependent on decreased chromatin accessibility at genes with motifs for STAT1 and IRF3 42 .…”

Hypoxia promotes osteogenesis by facilitating acetyl‐CoA‐mediated mitochondrial–nuclear communication

“…Given that chromatin architecture is involved in the regulation of gene transcription, we next sought to investigate whether the normoxia‐driven changes in the transcriptional profile were dictated by alterations in the chromatin landscape. Interestingly, two recent reports showed profound changes in chromatin accessibility following a switch in oxygen levels (Li et al , 2020 ; Batie et al , 2022 ). Since these two studies report opposite effects of hypoxia on chromatin accessibility, we next performed ATAC sequencing (ATAC‐seq) on hypoxia‐ and normoxia‐cultured cells (Fig EV1A and B ) to investigate how oxygen availability alters the chromatin accessibility profile of MSCs.…”

Involvement of hypoxia‐inducible factor activity in inevitable air‐exposure treatment upon differentiation in a three‐dimensional keratinocyte culture

“…Hypoxia-inducible factor is a well-characterized transcription factor consisting of two subunits; a tightly regulated a subunit and a constitutively expressed b subunit [18,19]. Three isoforms of the a subunit have been identified: HIF-1a, HIF-2a and HIF-3a.…”