Epitranscriptomic regulation of HIF-1: bidirectional regulatory pathways

Abstract

Background: Epitranscriptomics, the study of RNA modifications such as N⁶-methyladenosine (m⁶A), provides a novel layer of gene expression regulation with implications for numerous biological processes, including cellular adaptation to hypoxia. Hypoxia-inducible factor-1 (HIF-1), a master regulator of the cellular response to low oxygen, plays a critical role in adaptive and pathological processes, including cancer, ischemic heart disease, and metabolic disorders. Recent discoveries accent the dynamic interplay between m⁶A modifications and HIF-1 signaling, revealing a complex bidirectional regulatory network. While the roles of other RNA modifications in HIF-1 regulation remain largely unexplored, emerging evidence suggests their potential significance.

Main body: This review examines the reciprocal regulation between HIF-1 and epitranscriptomic machinery, including m⁶A writers, readers, and erasers. HIF-1 modulates the expression of key m⁶A components, while its own mRNA is regulated by m⁶A modifications, positioning HIF-1 as both a regulator and a target in this system. This interaction enhances our understanding of cellular hypoxic responses and opens avenues for clinical applications in treating conditions like cancer and ischemic heart disease. Promising progress has been made in developing selective inhibitors targeting the m⁶A-HIF-1 regulatory axis. However, challenges such as off-target effects and the complexity of RNA modification dynamics remain significant barriers to clinical translation.

Conclusion: The intricate interplay between m⁶A and HIF-1 highlights the critical role of epitranscriptomics in hypoxia-driven processes. Further research into these regulatory networks could drive therapeutic innovation in cancer, ischemic heart disease, and other hypoxia-related conditions. Overcoming challenges in specificity and off-target effects will be essential for realizing the potential of these emerging therapies.

Keywords: Cancer; Epitranscriptomics; HIF-1; Heart; Hypoxia-inducible factor-1; m6A.

Fig. 1

Overview of HIF-1 regulation. Under normoxia, PHDs hydroxylate HIF-1α, triggering pVHL-mediated degradation, while FIH-1 inhibits its transcriptional activity. In hypoxia, HIF-1α is stabilized, translocates into the nucleus, dimerizes with HIF-1β, and binds to HREs to activate genes involved in erythropoiesis, metabolism, angiogenesis, and cell survival

Fig. 2

Overview of RNA modifications and m⁶A regulation. The top left panel illustrates the most common RNA modifications, including N⁶-methyladenosine, N¹-methyladenosine, 5-methylcytidine, 7-methylguanosine, A-to-I editing, and pseudouridine. The top right panel lists key m⁶A regulatory enzymes, categorized as writers (METTL3, METTL14, WTAP, VIRMA), erasers (ALKBH5, FTO, ALKBH3), and readers (YTHDF1-3, YTHDC1-2, IGF2BP1-3). The bottom panel represents the dynamic cycle of m⁶A modification, where m⁶A writers deposit methyl groups on adenosine, readers recognize and interpret the modification, and erasers remove m⁶A to regulate RNA fate and function. ALKBH5: AlkB homolog 5; FTO: fat mass and obesity-associated; IGF2BP1-3: insulin-like growth factor 2 mRNA-binding protein 1–3; METTL3/14: methyltransferase-like 3/14; m⁶A: N⁶-methyladenosine; VIRMA: vir-like m⁶A methyltransferase associated; WTAP: Wilms’ tumor 1-associating protein; YTHDC1-2: YTH domain-containing protein 2; YTHDF1-3: YTH domain-containing family protein 1–3

Fig. 3

The reciprocal relationship of HIF-1 and m⁶A. This figure illustrates the interaction between m⁶A regulators and HIF-1α translation in a feedback loop. HIF-1 binds to HREs in genes encoding m⁶A writers, erasers, and readers, leading to their increased expression. These m⁶A regulators modify HIF1A mRNA, affecting its stability and translation, which in turn alters HIF-1α protein levels. This regulatory mechanism plays a crucial role in various physiological and pathological conditions, including cancer, ischemic heart disease, and white adipose tissue browning. ALKBH5: AlkB homolog 5; FTO: fat mass and obesity-associated; HIF-1/HIF1A: hypoxia-inducible factor 1; HRE: hypoxia response element; IGF2BP1/3: insulin-like growth factor 2 mRNA-binding protein 1/3; METTL3/14: methyltransferase-like 3/14; m⁶A: N⁶-methyladenosine; VIRMA: vir-like m⁶A methyltransferase associated; WTAP: Wilms’ tumor 1-associating protein; YTHDC2: YTH domain-containing protein 2; YTHDF1-2: YTH domain-containing family protein 1–2