Integrative analysis reveals extensive interactions among C2H2 zinc finger proteins at chromatin loop anchors

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ID: 333003
2026
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Abstract
Cys2-His2-zinc-finger proteins (C2H2-ZFPs) form the largest class of human transcription factors, yet their potential roles in higher-order genome organization remain poorly defined. To date, only a few C2H2-ZFPs, e.g. CTCF, have been implicated in chromatin organization. Here, we systematically examined the global relationship between C2H2-ZFPs and long-range chromatin interactions (LRIs). By integrating ChIP-seq datasets for 216 C2H2-ZFPs with genome-wide chromatin interaction maps, we find that >40% of human C2H2-ZFPs are significantly enriched at LRI anchors. Depletion of a subset of such C2H2-ZFPs is associated with altered expression of genes linked by the LRIs they occupy. To investigate whether protein-protein interactions (PPIs) contribute to this pattern, we generated a large-scale interactome using affinity purification-mass spectrometry, encompassing 345 C2H2-ZFPs, and LUMIER binary interaction assays for 204 C2H2-ZFPs, revealing extensive connectivity among the family members. Integrative analysis of PPIs, ChIP-seq, and chromatin interaction datasets revealed that interacting C2H2-ZFP pairs are significantly co-enriched at LRIs and frequently localize to the same or opposing loop anchors. Finally, we show that ∼35% of LRI-associated C2H2-ZFP binding sites overlap somatic mutations in cancer genomes. Together, our results reveal a widespread network of C2H2-ZFP interactions at chromatin loop anchors, providing an important resource for understanding chromatin organization.
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openalex_W7134247817 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Ernest Radovani, Syed Nabeel‐Shah, Edyta Marcon, Shuye Pu, Guoqing Zhong, Hua Tang, Hongbo Guo, Irene M. Kaplow, Andrew Emili, Timothy Hughes, Jack F. Greenblatt
Journal Nucleic Acids Research
Year 2026
DOI
10.1093/nar/gkag1004
URL
https://doi.org/10.1093/nar/gkag1004
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