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

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.