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<p>Non-canonical DNA structures add a dynamic layer of genome regulation beyond the classical double helix. I-motifs, cytosine-rich four-stranded DNA structures, are increasingly recognized as context-dependent regulators of genome function. Recent methodological advances, including i-motif-specific antibodies, in-cell NMR, and genome-wide profiling, have enabled their detection and functional interrogation. Here, we review progress in understanding i-motif formation, stability, and protein interactions, highlighting parallels and contrasts with G-quadruplex structures. We also discuss technical limitations, strategies for improving structure-specific resolution, and future opportunities to integrate biochemical, genomic, and imaging approaches to clarify the biological relevance and therapeutic potential of i-motifs.</p>

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The cellular landscape of i-motifs: genomic insights, methodological challenges, and the road ahead

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Pallabi Sengupta,
  • Nasim Sabouri

摘要

Non-canonical DNA structures add a dynamic layer of genome regulation beyond the classical double helix. I-motifs, cytosine-rich four-stranded DNA structures, are increasingly recognized as context-dependent regulators of genome function. Recent methodological advances, including i-motif-specific antibodies, in-cell NMR, and genome-wide profiling, have enabled their detection and functional interrogation. Here, we review progress in understanding i-motif formation, stability, and protein interactions, highlighting parallels and contrasts with G-quadruplex structures. We also discuss technical limitations, strategies for improving structure-specific resolution, and future opportunities to integrate biochemical, genomic, and imaging approaches to clarify the biological relevance and therapeutic potential of i-motifs.