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<p>The three-dimensional chromatin architecture is critical for gene regulation, yet factors beyond CCCTC-binding factor (CTCF) and cohesin remain poorly characterized. Here, we identify RFX5 as a novel regulator of chromatin organization. Using CRISPR-mediated <i>RFX5</i> knockout A375 cells, together with RNA-seq, ChIP-seq, ATAC-seq, QHR-4C, and Hi-C, we demonstrate that RFX5 binds to&#xa0;promoters and enhancers, co-localizes with CTCF, RAD21, and H3K27ac, maintains chromatin accessibility, and preserves chromatin loop strength. <i>RFX5</i> deletion alters the expression of ~2,000 genes, with strong suppression of cancer-associated genes and oncogenic pathways. Loss of RFX5 reduces CTCF/RAD21 occupancy and promoter accessibility at downregulated genes. Notably, RFX5 acts as an insulator to balance chromatin looping: its absence weakens enhancer–promoter contacts at oncogenic loci while enabling inappropriate long-range enhancer interactions at upregulated genes. Hi-C analysis reveals globally diminished loop strength, with only mild effects on TAD insulation and compartmentalization. These findings establish RFX5 as a key architectural factor that links 3D genome structure to transcriptional programs in cancer and immunity.</p>

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RFX5 as a regulator of spatial chromatin contacts and gene expression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月23日

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  • Xiao Ge,
  • Yijun Zhang,
  • Yiru Han,
  • Xuan Liu,
  • Zhilian Jia,
  • Yongjun Liang,
  • Yongming Wang

摘要

The three-dimensional chromatin architecture is critical for gene regulation, yet factors beyond CCCTC-binding factor (CTCF) and cohesin remain poorly characterized. Here, we identify RFX5 as a novel regulator of chromatin organization. Using CRISPR-mediated RFX5 knockout A375 cells, together with RNA-seq, ChIP-seq, ATAC-seq, QHR-4C, and Hi-C, we demonstrate that RFX5 binds to promoters and enhancers, co-localizes with CTCF, RAD21, and H3K27ac, maintains chromatin accessibility, and preserves chromatin loop strength. RFX5 deletion alters the expression of ~2,000 genes, with strong suppression of cancer-associated genes and oncogenic pathways. Loss of RFX5 reduces CTCF/RAD21 occupancy and promoter accessibility at downregulated genes. Notably, RFX5 acts as an insulator to balance chromatin looping: its absence weakens enhancer–promoter contacts at oncogenic loci while enabling inappropriate long-range enhancer interactions at upregulated genes. Hi-C analysis reveals globally diminished loop strength, with only mild effects on TAD insulation and compartmentalization. These findings establish RFX5 as a key architectural factor that links 3D genome structure to transcriptional programs in cancer and immunity.