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Peer-reviewedCC BY-NC-ND 4.0Communications Biology

High-resolution 3D chromatin maps reveal PTEN enhancer hubs bridged to the promoter through flanking anchors

  • Thibaut Matis1,2
  • Elodie Darbo1
  • Jessica Baud1
  • Noé Calais-Yager3
  • Delfine Lafon2
  • Valérie Prouzet-Mauléon1,3
  • Sandrine Dabernat1,4,5
  • Michel Longy1
  • Nicolas Sévenet1,2,5
5 affiliations
  1. 1University of Bordeaux, INSERM, BRIC, U 1312, Bordeaux, France
  2. 2Cancer Genetics Unit, Institut Bergonié, Bordeaux, France
  3. 3CRISP’edit, TBMCore, CNRS UAR3427, INSERM US005, University of Bordeaux, Bordeaux, France
  4. 4CHU Bordeaux (Biochemistry Laboratory), Bordeaux, France
  5. 5Univ. Bordeaux, Faculty of Pharmacy, Bordeaux, France
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Abstract

Understanding the cis-regulatory architecture of tumor suppressor loci is crucial for elucidating the mechanisms of gene dysregulation in cancer and genetic syndromes. Despite its central role in multiple cancers and PTEN Hamartoma Tumor Syndrome (PHTS), the regulatory landscape of the PTEN locus remains largely uncharacterized. Using high-resolution Tiled-C and multi-omics profiling across 11 human cell lines, including two patient-derived models, we map a 3 Mb region surrounding the PTEN topologically associated domain (TAD). We identify seven chromatin hubs anchoring eleven enhancers, whose CRISPR interference substantially reduces PTEN expression. In these hubs, most enhancers preferentially interact with each other rather than the PTEN promoter, forming a spatially organized enhancer network. Notably, enhancers are not in direct contact with the promoter but are brought into proximity through associated flanking chromatin anchor points enriched in REX elements, enabling gene regulation by bridging distal regulatory elements. Lastly, while structural variants can disrupt TAD, PTEN mutations alone only slightly reinforce intra-TAD contacts without changing the structure. These findings provide the first high-resolution map of PTEN enhancer hubs, reveal new principles of enhancer cooperation and long-range gene regulation, and delineate candidate regions whose disruption may contribute to PHTS and PTEN-driven tumorigenesis.

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Cite

BibTeXRIS
BibTeX
@article{matis2026highresolution,
  title = {{High-resolution 3D chromatin maps reveal PTEN enhancer hubs bridged to the promoter through flanking anchors}},
  author = {Thibaut Matis and Elodie Darbo and Jessica Baud and Noé Calais-Yager and Delfine Lafon and Valérie Prouzet-Mauléon and Sandrine Dabernat and Michel Longy and Nicolas Sévenet},
  journal = {Communications Biology},
  year = {2026},
  month = jun,
  doi = {10.1038/s42003-026-10533-0},
  url = {https://doi.org/10.1038/s42003-026-10533-0},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - High-resolution 3D chromatin maps reveal PTEN enhancer hubs bridged to the promoter through flanking anchors
AU  - Thibaut Matis
AU  - Elodie Darbo
AU  - Jessica Baud
AU  - Noé Calais-Yager
AU  - Delfine Lafon
AU  - Valérie Prouzet-Mauléon
AU  - Sandrine Dabernat
AU  - Michel Longy
AU  - Nicolas Sévenet
PY  - 2026
DA  - 2026/06/25
JO  - Communications Biology
DO  - 10.1038/s42003-026-10533-0
UR  - https://doi.org/10.1038/s42003-026-10533-0
AB  - Understanding the cis-regulatory architecture of tumor suppressor loci is crucial for elucidating the mechanisms of gene dysregulation in cancer and genetic syndromes. Despite its central role in multiple cancers and PTEN Hamartoma Tumor Syndrome (PHTS), the regulatory landscape of the PTEN locus remains largely uncharacterized. Using high-resolution Tiled-C and multi-omics profiling across 11 human cell lines, including two patient-derived models, we map a 3 Mb region surrounding the PTEN topologically associated domain (TAD). We identify seven chromatin hubs anchoring eleven enhancers, whose CRISPR interference substantially reduces PTEN expression. In these hubs, most enhancers preferentially interact with each other rather than the PTEN promoter, forming a spatially organized enhancer network. Notably, enhancers are not in direct contact with the promoter but are brought into proximity through associated flanking chromatin anchor points enriched in REX elements, enabling gene regulation by bridging distal regulatory elements. Lastly, while structural variants can disrupt TAD, PTEN mutations alone only slightly reinforce intra-TAD contacts without changing the structure. These findings provide the first high-resolution map of PTEN enhancer hubs, reveal new principles of enhancer cooperation and long-range gene regulation, and delineate candidate regions whose disruption may contribute to PHTS and PTEN-driven tumorigenesis.
SN  - 2399-3642
ER  -