KBG syndrome-associated protein ANKRD11 regulates SETD5 expression to modulate rRNA levels and translation. Sashiyama et al

The haploinsufficiency of ANKRD11 or SETD5 is implicated in KBG syndrome characterized by intellectual disability, autism spectrum disorders, and skeletal abnormalities. However, the molecular mechanisms linking these protein deficiencies to KBG syndrome are not fully understood. Here we report that ANKRD11-deficient neural cells exhibit reduced ribosomal RNA (rRNA) and translational activity. ANKRD11 is primarily localized outside the nucleolus, where rDNA transcription occurs, suggesting an indirect role in regulating rRNA expression. Instead, ANKRD11 increases SETD5 expression known to enhance rRNA production. Mechanistically, ANKRD11 interacts with the Setd5 promoter, recruiting WDR5, a component of the histone H3 lysine 4 (H3K4) methyltransferase complex involved in transcriptional activation. Correspondingly, reduced H3K4 methylation on the Setd5 promoter correlates with diminished SETD5 expression in ANKRD11-deficient cells Overexpression of ANKRD11 or SETD5 restores rRNA levels and translational activity. These findings underscore the role of the ANKRD11-SETD5 axis in alleviating KBG syndrome pathogenesis, offering insights into potential therapeutic targets.