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Peer-reviewedCC BY 4.0Nucleic Acids Research

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

  • Ernest Radovani1,2
  • Syed Nabeel-Shah1
  • Edyta Marcon1,3
  • Shuye Pu1
  • Guoqing Zhong1
  • Hua Tang1
  • Hongbo Guo1
  • Irene M Kaplow4,5
  • Andrew Emili1,2
  • Timothy R Hughes1,2
  • Jack F Greenblatt1,2
5 affiliations
  1. 1Donnelly Centre, University of Toronto , Toronto, ON M5S 3E1 ,
  2. 2Department of Molecular Genetics, University of Toronto , Toronto, ON M5S 1A8 ,
  3. 3Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto , Toronto, ON M5S 1A8 ,
  4. 4Department of Computer Science, Stanford University , Stanford, CA 94305 ,
  5. 5Ray and Stephanie Lane Department of Computational Biology, Carnegie Mellon University , Pittsburgh, PA 15213 ,
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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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Cite

BibTeXRIS
BibTeX
@article{radovani2026integrative,
  title = {{Integrative analysis reveals extensive interactions among C2H2 zinc finger proteins at chromatin loop anchors}},
  author = {Ernest Radovani and Syed Nabeel-Shah and Edyta Marcon and Shuye Pu and Guoqing Zhong and Hua Tang and Hongbo Guo and Irene M Kaplow and Andrew Emili and Timothy R Hughes and Jack F Greenblatt},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag1004},
  url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1004/8937191},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Integrative analysis reveals extensive interactions among C2H2 zinc finger proteins at chromatin loop anchors
AU  - Ernest Radovani
AU  - Syed Nabeel-Shah
AU  - Edyta Marcon
AU  - Shuye Pu
AU  - Guoqing Zhong
AU  - Hua Tang
AU  - Hongbo Guo
AU  - Irene M Kaplow
AU  - Andrew Emili
AU  - Timothy R Hughes
AU  - Jack F Greenblatt
PY  - 2026
DA  - 2026/10/01
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag1004
UR  - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1004/8937191
AB  - 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.
SN  - 0305-1048
SN  - 1362-4962
ER  -