A PHD-zinc finger-mediated mechanism for PHF21B recognition of H3K36me3.

HF21B is an epigenetic reader that modulates synaptic plasticity-related genes and social memory (1). Although PHF21B is known to bind H3K36me3, the domain responsible for this interaction has remained uncharacterized. Here, we used co-immunoprecipitation with PHF21B deletion mutants in HEK293T cells to show that the PHD-zinc finger domain is essential for H3K36me3 recognition, whereas the C-terminal coiled-coil region is dispensable. These findings identify the PHD-zinc finger domain as the critical H3K36me3-binding module of PHF21B, with implications for neurological disorders linked to chromosome 22q13.3 deletion, including Phelan-McDermid syndrome (2, 3).