TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons.

Publication Type:

Journal Article


Nature, Volume 623, Issue 7987, p.633-642 (2023)


Animals, Animals, Newborn, Cell Line, Chromatin, Co-Repressor Proteins, Endogenous Retroviruses, Epigenesis, Genetic, Gene Expression Profiling, Gene Silencing, Genome, Histone Deacetylases, Histones, Humans, Intracellular Signaling Peptides and Proteins, Lysine, Methylation, Mice, Protein Domains, Retroelements, Terminal Repeat Sequences


<p>Trimethylation of histone H3 lysine&thinsp;9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development. H3K9me3 also provides an essential mechanism for silencing transposable elements. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. ) and MPP8 (refs. )) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome. Here we report that trinucleotide-repeat-containing&thinsp;18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class&thinsp;I (ERV1) elements such as LTR12 (ref. ). 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.</p>