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

Jackson B Trotman; Elizabeth W Abrash; McKenzie M Murvin; Aki K Braceros; Shuang Li; Samuel P Boyson; Ryan T Salcido; Rachel E Cherney; Steven R Bischoff; Kyle Kaufmann; Quinn E Eberhard; Zhiyue Zhang; Dale O Cowley; J Mauro Calabrese

doi:10.1016/j.molcel.2025.02.014

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

Mol Cell. 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.

Publication types

Comparative Study

MeSH terms

Animals
Chromatin* / genetics
Chromatin* / metabolism
Gene Silencing
Heterogeneous-Nuclear Ribonucleoprotein K / genetics
Heterogeneous-Nuclear Ribonucleoprotein K / metabolism
Mice
Mouse Embryonic Stem Cells / metabolism
Polycomb Repressive Complex 1 / genetics
Polycomb Repressive Complex 1 / metabolism
Polycomb Repressive Complex 2* / genetics
Polycomb Repressive Complex 2* / metabolism
Polycomb-Group Proteins / genetics
Polycomb-Group Proteins / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

RNA, Long Noncoding
XIST non-coding RNA
Polycomb Repressive Complex 2
Chromatin
Transcription Factors
Heterogeneous-Nuclear Ribonucleoprotein K
Polycomb-Group Proteins
Polycomb Repressive Complex 1

Abstract

Publication types

MeSH terms

Substances

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