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TNRC18 recognizes H3K9me3 to mediate transposable elements silencing at ERV regions [CAGE-seq]

ABSTRACT: Trimethylation of histone H3 lysine 9 (H3K9me3) is critical for regulation of gene repression and heterochromatin formation, cell-fate determination, and organismal development. In particular, H3K9me3 provides an essential mechanism for silencing various transposon elements (TEs). However, previous studies showed that the canonical H3K9me3 readers (e.g. HP1 and MPP8) play rather limited roles in silencing endogenous retroviruses (ERVs), one of major TE classes in the mammalian genome. Here, we report that Trinucleotide Repeat Containing 18 (TNRC18), a previously under-studied chromatin regulator, recognizes H3K9me3 and directly binds ERVs, mediating ERV silencing. Our biochemical, biophysical and structural studies identified the C-terminal Bromo Adjacent Homology (BAH) domain of TNRC18 (TNRC18BAH) as a H3K9me3-specific reader, and its N-terminal segment as a platform for direct recruitment of co-repressors such as TRIM28 and HDAC-Sin3-NCoR complexes, thereby enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18BAH-mediated H3K9me3 engagement caused neonatal lethality in mice and, in multiple mammalian cell models, led to de-repressed expression of ERVs, affecting the landscape of cis-regulatory elements and thus gene-expression programs. Collectively, this study describes a previously-unknown TNRC18BAH-directed H3K9me3-sensing pathway, which operates to epigenetically silence the evolutionarily young ERVs, thereby exerting profound impacts on host genome integrity, transcriptomic regulation, immunity, and development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205505 | GEO | 2023/07/24

REPOSITORIES: GEO

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TNRC18 recognizes H3K9me3 to mediate transposable elements silencing at ERV regions [WGBS]

Project description:Trimethylation of histone H3 lysine 9 (H3K9me3) is critical for regulation of gene repression and heterochromatin formation, cell-fate determination, and organismal development. In particular, H3K9me3 provides an essential mechanism for silencing various transposon elements (TEs). However, previous studies showed that the canonical H3K9me3 readers (e.g. HP1 and MPP8) play rather limited roles in silencing endogenous retroviruses (ERVs), one of major TE classes in the mammalian genome. Here, we report that Trinucleotide Repeat Containing 18 (TNRC18), a previously under-studied chromatin regulator, recognizes H3K9me3 and directly binds ERVs, mediating ERV silencing. Our biochemical, biophysical and structural studies identified the C-terminal Bromo Adjacent Homology (BAH) domain of TNRC18 (TNRC18BAH) as a H3K9me3-specific reader, and its N-terminal segment as a platform for direct recruitment of co-repressors such as TRIM28 and HDAC-Sin3-NCoR complexes, thereby enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18BAH-mediated H3K9me3 engagement caused neonatal lethality in mice and, in multiple mammalian cell models, led to de-repressed expression of ERVs, affecting the landscape of cis-regulatory elements and thus gene-expression programs. Collectively, this study describes a previously-unknown TNRC18BAH-directed H3K9me3-sensing pathway, which operates to epigenetically silence the evolutionarily young ERVs, thereby exerting profound impacts on host genome integrity, transcriptomic regulation, immunity, and development.

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MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells

Project description:Deciphering the mechanisms that control the pluripotent ground state is key for understanding embryonic development. Nonetheless, the epigenetic regulation of ground-state mouse embryonic stem cells (mESCs) is not fully understood. Here, we identify the epigenetic protein MPP8 as being essential for ground-state pluripotency. Its depletion leads to cell cycle arrest and spontaneous differentiation. MPP8 has been suggested to repress LINE1 elements by recruiting the human silencing hub (HUSH) complex to H3K9me3-rich regions. Unexpectedly, we find that LINE1 elements are efficiently repressed by MPP8 lacking the chromodomain, while the unannotated C-terminus is essential for its function. Moreover, we show that SETDB1 recruits MPP8 to its genomic target loci, whereas transcriptional repression of LINE1 elements is maintained without retaining H3K9me3 levels. Taken together our findings demonstrate that MPP8 protects the DNA-hypomethylated pluripotent ground state through its association with the HUSH core complex, however, independently of detectable chromatin binding and maintenance of H3K9me3.

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MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells

Project description:Deciphering the mechanisms that control the pluripotent ground state is key for understanding embryonic development. Nonetheless, the epigenetic regulation of ground-state mouse embryonic stem cells (mESCs) is not fully understood. Here, we identify the epigentic protein MPP8 as being essential for ground-state pluripotency. Its depletion leads to cell cycle arrest and spontaneous differentiation. MPP8 has been suggested to repress LINE1 elements by recruiting the human silencing hub (HUSH) complex to H3K9me3-rich regions. Unexpectedly, we find that LINE1 elements are efficiently repressed by MPP8 lacking the chromodomain, while the unannotated C-terminus is essential for its function. Moreover, we show that SETDB1 recruits MPP8 to its genomic target loci, whereas transcriptional repression of LINE1 elements is maintained without retaining H3K9me3 levels. Taken together our findings demonstrate that MPP8 protects the DNA-hypomethylated pluripotent ground state through its association with the HUSH core complex, however, independently of detectable chromatin binding and maintenance of H3K9me3.

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