KBG syndrome-associated protein ANKRD11 regulates SETD5 expression to modulate rRNA levels and translation

ANKRD11 haploinsufficiency is implicated in KBG syndrome, characterized by intellectual disability, autism spectrum disorders, and skeletal abnormalities. While <i>SETD5</i> mutations are linked to a distinct clinical disorder, they also appear in KBG-like cases, suggesting shared molecular pathways. Here, we show that ANKRD11-deficient neural cells exhibit reduced ribosomal RNA (rRNA) and translation. Although ANKRD11 primarily localizes outside the nucleolus, where rDNA transcription occurs, it indirectly promotes rRNA expression by upregulating SETD5, a transcriptional activator of rRNA. Mechanistically, ANKRD11 interacts with the <i>Setd5</i> promoter and recruits WDR5, a component of the histone H3 lysine 4 (H3K4) methyltransferase complex involved in transcriptional activation. Correspondingly, reduced H3K4 methylation on the <i>Setd5</i> 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.