Hypoxic Regulation of Gene Transcription and Chromatin: Cause and Effect

Abstract

Cellular responses to low oxygen (hypoxia) are fundamental to normal physiology and to the pathology of many common diseases. Hypoxia-inducible factor (HIF) is central to this by enhancing the transcriptional activity of many hundreds of genes. The cellular response to HIF is cell-type-specific and is largely governed by the pre-existing epigenetic landscape. Prior to activation, HIF-binding sites and the promoters of HIF-target genes are already accessible, in contact with each other through chromatin looping and display markers of activity. However, hypoxia also modulates the epigenetic environment, both in parallel to and as a consequence of HIF activation. This occurs through a combination of oxygen-sensitive changes in enzyme activity, transcriptional activation of epigenetic modifiers, and localized recruitment to chromatin by HIF and activated RNApol2. These hypoxic changes in the chromatin environment may both contribute to and occur as a consequence of transcriptional regulation. Nevertheless, they have the capacity to both modulate and extend the transcriptional response to hypoxia.

Mechanisms of Binding Specificity among bHLH Transcription Factors

“…Several bHLH factors, such as USF1/2 [213], TCF3 (in B cells) [213], yeast Pho4 [214], HIF1A-ARNT [215], and MYC [138,142,216] among others, have shown to preferentially target accessible chromatin. This preference for open chromatin is particularly evident when comparing binding of TFs across different cell types.…”

“…Cytosines in CpG sites frequently present a methyl group bound to their 5th position, which can be progressively oxidized to 5-hydroximethylcythosine (5hmC), then 5-formylcytosine (5fC), and then be subsequently transformed into 5-carboxylcytosine (5caC) [230]. Symmetrical methylation of the central CpG of E-boxes has shown to prevent Myc-Max, Max-Max and HIF1A-ARNT binding to DNA [215,[231][232][233]. In the case of Max homodimers, and oxidation to a 5caC restores the affinity to the level of the unmodified cytosine [233].…”

Hypoxia – as a Possible Regulator of the Activity of Epicardial Mesothelial Cells After Myocardial Infarction

“…Ключевым патофизиологическим компонентом ИМ является гипоксия, которая активирует сигнальный путь HIF [36] и запускает широкий спектр клеточных реакций, включая регуляцию экспрессии генов и посттрансляционные модификации белков. Для изучения влияния тканевой гипоксии на активность клеток эпикарда были исследованы срезы сердец животных, полученных после моделирования ИМ.…”

Multiple roles for peptidylglycine α‐amidating monooxygenase in the response to hypoxia

“…In addition, PAM is among the top 176 human genes identified by both HIF1A-ChIP-seq and HIF2A/EPAS1-ChIPseq (Bono & Hirota, 2020). Based on multiple studies, a consensus hypoxia response element (HRE) has been defined (Figure 8a; Dengler et al, 2014;Kaelin et al, 2016;Kindrick & Mole, 2020; F I G U R E 8 Identification of putative hypoxia-response elements (HREs) in the human and mouse PAM genes. (a) The consensus HRE sequence is VBRCGTG where R═A or G; B═C, G or T; V═C, G or A (Dengler et al, 2014;Kindrick & Mole, 2020;Wenger et al, 2005).…”

“…. Functional HREs are most commonly found in the proximal 2 kb of the 5ʹ-flanking region, with some within a few nucleotides (nts) of the transcriptional initiation site, but are also found in 5ʹ-untranslated regions (UTRs), nearby intervening sequences and distant 3ʹ-UTRs (Kindrick & Mole, 2020;Wenger et 2005). Consistent with this, three of the five putative HREs identified in hPAM are in its 5ʹ-UTR, with two of the putative sites in the upstream genomic region (Figure 8b).…”