THE I-MOTIF TWIST: A NEW GENE REGUALTION PARADIGM

 Genetic stability is paramount for preserving the integrity of genetic information and preventing mutation that can lead to diseases like cancer and developmental disorders. Understanding the genome architecture and function it is paramount to locate the regulatory elements in human genome, as these element plays a pivotal role in controlling gene expression and ensuring accurate DNA replication. Key structures like telomeres, centromeres and DNA repair complex safeguard genomic stability and maintaining cellular functions. While, controlling genetic variation evolves mutation and excessive instability. Therefore,  elucidating the regulatory elements and mechanism that maintain genomic stability is vital for preventing disorders.

I-motif (iMs) structure and guanine rich G- quadraplex structures(G-4s) have been identified as two important regulatory elements which plays an important role in regulating gene expression, DNA replication and regions of DNA like telomeric and centromeric. These structures have also linked to various human health conditions.

Unlike normal double stranded DNA, these i-Ms are tetrameric structure formed by the folding of cytosine-rich sequence. This structure is stabilized by hemi-protonated cytosine-cytosine base pair in which one of the cytosine bases is protonated (gain proton), whereas other is unprotonated. For a long time, it was believed that these structures are formed only in acidic condition; however, recent studies have shown that i-Ms can be formed even under normal condition.

Figure 1. Identification of iM structures in human genomic DNA.

In this study, researchers use a specific anti-body known as iMab, to map the location of iMs in the DNA using immuno-precipitation. The results were astonishing, it had been found that iMs are widely spread across human genome. In addition to that, it was found that iMs and G4s overlap suggesting that these two can often appear together in DNA. It was also found that both structures are found near transcription start site (TSS), where transcription is initiated. However, iMs are less common near TSS compared to G4s, this supports the idea of G4s are involved in timing and process off cell division, while iMs contribute to the structural organisation of gene, which affects the gene regulation. Furthermore, it was observed that i-motifs are wildly spread across the genome where active genes are present. Conversely, i-motif are less likely to found in regions with repressed or inactive genes, suggesting that iMs can involve in both active and repressed gene regulation. Finally, the study revealed that i-motis are associated with genes more active during the G0 and G1 phase.

This discovery of i-motif and their role in gene regulation can lead to further exploration of their function in and how they might be targeted for therapeutic purposes. Whether it’s for diagnosing or developing new treatments.

Image Credits:

1. Cloudfront,https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20180621100350/ri/673/picture/2018/6/Chris_Hammang.jpg
2. .Embopress,https://www.embopress.org/cms/10.1038/s44318-024-00210-5/asset/b9b06e3b-1453-4aaa-ac8e-02b710aed697/assets/graphic/44318_2024_210_fig1_html.png

Reference:

1. Peña Martinez CD, Zeraati M, Rouet R, Mazigi O, Gloss B, Chan CL, Bryan TM, Smith NM, Dinger ME, Kummerfeld S, Christ D. Human genomic DNA is widely interspersed with i-motif structures. BioRxiv. 2022 Apr 14:2022-04.