TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons

Shuai Zhao, Jiuwei Lu, Bo Pan, Huitao Fan, Stephanie D. Byrum, Chenxi Xu, Arum Kim, Yiran Guo, Krishna L. Kanchi, Weida Gong, Tongyu Sun, Aaron J. Storey, Nathaniel T. Burkholder, Samuel G. Mackintosh, Peyton C. Kuhlers, Ricky D. Edmondson, Brian D. Strahl, Yarui Diao, Alan J. Tackett, Jesse R. Raab, Ling Cai, Jikui Song () and Gang Greg Wang ()
Additional contact information
Shuai Zhao: Duke University School of Medicine
Jiuwei Lu: University of California
Bo Pan: Duke University School of Medicine
Huitao Fan: University of North Carolina at Chapel Hill School of Medicine
Stephanie D. Byrum: University of Arkansas for Medical Sciences
Chenxi Xu: Duke University School of Medicine
Arum Kim: Duke University School of Medicine
Yiran Guo: Duke University School of Medicine
Krishna L. Kanchi: University of North Carolina at Chapel Hill School of Medicine
Weida Gong: University of North Carolina at Chapel Hill School of Medicine
Tongyu Sun: Duke University School of Medicine
Aaron J. Storey: University of Arkansas for Medical Sciences
Nathaniel T. Burkholder: University of North Carolina at Chapel Hill School of Medicine
Samuel G. Mackintosh: University of Arkansas for Medical Sciences
Peyton C. Kuhlers: University of North Carolina at Chapel Hill School of Medicine
Ricky D. Edmondson: University of Arkansas for Medical Sciences
Brian D. Strahl: University of North Carolina at Chapel Hill School of Medicine
Yarui Diao: Duke University School of Medicine
Alan J. Tackett: University of Arkansas for Medical Sciences
Jesse R. Raab: University of North Carolina at Chapel Hill School of Medicine
Ling Cai: Duke University School of Medicine
Jikui Song: University of California
Gang Greg Wang: Duke University School of Medicine

Nature, 2023, vol. 623, issue 7987, 633-642

Abstract: Abstract Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1–4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5–9) and MPP8 (refs. 10–12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC–Sin3–NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.

Date: 2023
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06688-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:623:y:2023:i:7987:d:10.1038_s41586-023-06688-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06688-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().