Advances in Hypoxia-Inducible Factor Biology Hani Choudhry, Adrian L. Harris  Cell Metabolism  Volume 27, Issue 2, Pages 281-298 (February 2018) DOI: 10.1016/j.cmet.2017.10.005 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Examples of Regulatory Mechanisms between lncRNAs and HIFs (A) HIF-2α binds HRE at the promoter region of NEAT1 to induce its expression under hypoxia. Upregulated NEAT1 increases the formation of paraspeckle bodies. On the other hand, upon hypoxia the editing of RNA is also increased. Hyper-edited RNA molecules (in particular A to I editing) bind to paraspeckle bodies and retained in the nucleus, thus inhibiting their translation. NB, only detected in one cell type (Chen and Carmichael, 2009). (B) Hypoxia downregulates lncRNA-LET expression through hypoxia-induced HDAC3, a HIF-1α-dependent gene. Hypoxia-induced HDAC3 reduces the histone H3 and H4 acetylation-mediated modulation at the promoter region of LncRNA-LET, which consequently suppresses its expression. Decreased lncRNA-LET expression increases the abundance of NF90 protein and hence upregulates the HIF-1α level. (C) Hypoxia induces lincRNA-P21 expression in a HIF-1α-dependent manner. Hypoxia- induced lincRNA-P21 binds to VHL and HIF-1α that causes disassociation of VHL and HIF-1α, therefore inhibiting proteasome-dependent degradation of HIF-1α under hypoxia. LincRNA-p21 modulates the Warburg effect through regulating expression of a number of glycolysis-related genes. (D) Signal from Heparin-binding EGF (HB-EGF) triggers “EGFR:GPNMB” heterodimerization. This leads to the recruitment of LINK-A, which interacts with both BRK and LRRK2 to facilitate phosphorylation of HIF1α and promotes glycolysis reprogramming in TNBC. Cell Metabolism 2018 27, 281-298DOI: (10.1016/j.cmet.2017.10.005) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Bidirectional Interactions between Circadian Clock and HIF Pathways Under hypoxia, HIF-1α heterodimerizes with HIF-1β in nucleus and binds to HREs in the promoters of hypoxia-induced genes. Upon recruitment of CBP/P300 (co-activator), the HIF-1α:HIF-1β complex drives the transcription of target genes such as glycolysis-related genes and some circadian clock genes such as PERs, CRYs, and DECs. On the other hand, BMAL1 heterodimerizes with CLOCK to form a BMAL1:CLOCK complex which binds at E-box-containing motifs and transactivates the clock-controlled genes such as PERs, CRYs, REV-ERB, and RORs, including HIF-1α. CBP/P300 acts as co-activator to induce the activation. There are a number of interconnected feedback loops between HIF and circadian clock pathways that regulate the circadian transcription. The key feedback is a native loop of PER and CRY (transcriptionally activated by HIF and by BMAL1:CLOCK) that leads to the repression of CLOCK:BMAL1-mediated transcription. The other feedback loop is by ROR, which activates BMAL1:CLOCK by binding the ROR-elements (RORE). In addition, ROR physically interacts with HIF-1α, hence inducing the stabilization and transcriptional activation of HIF-1α. REV-ERB acts as a repressor for BMAL1 transcription by competing at the same ROR sequence. HIF-1α-dependent DECs also negatively feedback by suppressing BMAL1:CLOCK transactivation. These interactions and feedback loops provide strong evidence that HIF plays an important role in modulating the circadian rhythm. Cell Metabolism 2018 27, 281-298DOI: (10.1016/j.cmet.2017.10.005) Copyright © 2017 Elsevier Inc. Terms and Conditions