Auto-methylation of the histone methyltransferase SetDB1 at its histone-mimic motifs ensures formation of extended and stable heterochromatin domains

ABSTRACT: Heterochromatin plays a critical role in nuclear organization and the regulation of gene expression by directing 3D genome organization, regulating lineage-specific gene expression, and ensuring the repression of transposable elements. The primary mark of heterochromatin, trimethylation of histone H3 at lysine 9 (H3K9me3), is deposited by histone methyltransferases, such as SetDB1, and serves as a binding platform for readers, most notably HP1 family proteins. Using a reporter system to monitor the dynamics of heterochromatin establishment and maintenance, we demonstrated that transient tethering of HP1 triggers the SetDB1-dependent establishment of epigenetically stable heterochromatin. We discovered that a direct physical interaction between HP1 and SetDB1 is mediated by the auto-methylation of two conserved histone mimic motifs located in unstructured regions of SetDB1. HP1 binds these SetDB1 motifs using the same molecular interface it employs to recognize the modified histone tail. SetDB1 auto-methylation is essential for H3K9me3 spreading and the epigenetic stability of heterochromatin, including the processes of X-chromosome inactivation and the negative feedback regulation of a large gene family encoding KRAB-ZNF transcriptional repressors. Thus, the primary heterochromatin mark is not limited to nucleosomes but is also deployed on the mark’s writer itself fostering a direct physical interaction between the writer and the reader and ensuring key properties of heterochromatin: its spreading to establish extended domains and its stable maintenance through cell divisions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287389 | GEO | 2026/09/24

REPOSITORIES: GEO