Isogenic comparison of Airn and Xist reveals core principles of Polycomb recruitment by lncRNAs

Affiliations

¹ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
² Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Mechanistic, Interdisciplinary Studies of Biological Systems, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Mechanistic, Interdisciplinary Studies of Biological Systems, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Animal Models Core, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶ Animal Models Core, University of North Carolina, Chapel Hill, NC 27599, USA; Transviragen, Inc., Chapel Hill, NC 27599, USA.
⁷ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁸ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Animal Models Core, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Transviragen, Inc., Chapel Hill, NC 27599, USA.
¹⁰ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: jmcalabr@med.unc.edu.

PMID: 40118040
PMCID: PMC11932450 (available on 2026-03-20)
DOI: 10.1016/j.molcel.2025.02.014

Comparative Study

Isogenic comparison of Airn and Xist reveals core principles of Polycomb recruitment by lncRNAs

Jackson B Trotman et al. Mol Cell. 2025.

. 2025 Mar 20;85(6):1117-1133.e14.

doi: 10.1016/j.molcel.2025.02.014.

Authors

Affiliations

¹ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
² Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Mechanistic, Interdisciplinary Studies of Biological Systems, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Mechanistic, Interdisciplinary Studies of Biological Systems, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Animal Models Core, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶ Animal Models Core, University of North Carolina, Chapel Hill, NC 27599, USA; Transviragen, Inc., Chapel Hill, NC 27599, USA.
⁷ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁸ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Animal Models Core, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Transviragen, Inc., Chapel Hill, NC 27599, USA.
¹⁰ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: jmcalabr@med.unc.edu.

PMID: 40118040
PMCID: PMC11932450 (available on 2026-03-20)
DOI: 10.1016/j.molcel.2025.02.014

Abstract

The mechanisms and biological roles of Polycomb repressive complex (PRC) recruitment by long noncoding RNAs (lncRNAs) remain unclear. To gain insight, we expressed two lncRNAs that recruit PRCs to multi-megabase domains, Airn and Xist, from an ectopic locus in mouse stem cells and compared effects. Unexpectedly, ectopic Airn recruited PRC1 and PRC2 to chromatin with a potency resembling Xist yet did not repress genes. Compared with PRC2, PRC1 was more proximal to Airn and Xist, where its enrichment over C-rich elements required the RNA-binding protein HNRNPK. Fusing Airn to Repeat A, the domain required for gene silencing by Xist, enabled gene silencing and altered local patterns but not relative levels of PRC-directed modifications. Our data suggest that, endogenously, Airn recruits PRCs to maintain rather than initiate gene silencing, that PRC recruitment occurs independently of Repeat A, and that protein-bridged interactions, not direct RNA contacts, underlie PRC recruitment by Airn, Xist, and other lncRNAs.

Keywords: Airn; Kcnq1ot1; PRC1; PRC2; Polycomb; Repeat A; Xist; lncRNA; repression; silencing; transcription.

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Conflict of interest statement

Declaration of interests D.O.C. is employed by, has equity ownership in, and serves on the board of directors of TransViragen, the company contracted by UNC-Chapel Hill to manage its Animal Models Core Facility.

References

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Isogenic comparison of Airn and Xist reveals core principles of Polycomb recruitment by lncRNAs

Affiliations

Isogenic comparison of Airn and Xist reveals core principles of Polycomb recruitment by lncRNAs

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous