i-Motifs as regulatory switches: Mechanisms and implications for gene expression

i-Motifs, cytosine-tetrads, or C-quadruplexes are intercalated structures formed by base pairing between cytosine and protonated cytosine. These structures demonstrate increased stability in acidic environments due to the presence of the latter cytosinium group (i.e., the protonated cytosine). Research has shown that i-motifs are typically disrupted or destabilized at physiological pH levels (7.0-7.4), which makes their potential formation in the nucleus and their biological relevance uncertain. However, in 2018, it was demonstrated that i-motifs exist within the nucleus under physiological conditions, with various intracellular factors contributing to their stability. Identification of i-motifs in the nucleus and their association with gene promoters-particularly with those of proto-oncogenes-has generated significant interest in their potential regulatory functions. Additionally, recent studies suggest that i-motifs may function as switches for gene expression, influencing gene regulation through their folding and stabilization or unfolding and destabilization. This review aims to delve into these mechanisms to improve our understanding of the physiological significance of i-motifs.