Other
23 Authors
- Byrum SD,
- Wang GG,
- Kuhlers PC,
- Storey AJ,
- Song J,
- Fan H,
- Burkholder NT,
- Sun T,
- Raab JR,
- Edmondson RD,
- Cai L,
- Xu C,
- Tackett AJ,
- Kim A,
- Guo Y,
- Pan B,
- Mackintosh SG,
- Lu J,
- Diao Y,
- Kanchi KL,
- Zhao S,
- Strahl BD,
- Gong W
| First Author | Zhao S | Year | 2023 |
| Journal | Nature | Volume | 623 |
| Issue | 7987 | Pages | 633-642 |
| PubMed ID | 37938770 | Mgi Jnum | J:342966 |
| Mgi Id | MGI:7561952 | Doi | 10.1038/s41586-023-06688-z |
| Citation | Zhao S, et al. (2023) TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons. Nature 623(7987):633-642 |
| abstractText | Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development(1). H3K9me3 also provides an essential mechanism for silencing transposable elements(1-4). 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 genome(13). 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. |
