Condensates of the chromatin regulator ANKRD11 restrict hypertranscribed genes to safeguard development.
Genes that define cell identity are often highly transcribed, but how their activity is regulated to prevent pathological dysregulation remains elusive. Using a two-tiered genetic screen, we identify a network of genes regulating hypertranscribed loci, which is notably enriched for genes mutated in developmental disorders. Among these, ANKRD11, a chromatin regulator haploinsufficient in KBG syndrome, exerts progressively stronger repression on more highly transcribed genes. ANKRD11 enriches around hypertranscribed loci and forms biomolecular condensates via charge-block-patterned intrinsically disordered regions. These condensates spatially sequester elongation factors away from RNA polymerase II, thereby restricting transcription elongation. In mice, Ankrd11 loss abrogates this restriction, causing aberrant developmental gene activation, disrupted organogenesis, and embryonic lethality. Critically, KBG patient cells with ANKRD11 mutations show defective condensate formation and consequent overactivation of hypertranscribed genes. These results uncover a condensate-mediated mechanism that restricts hypertranscribed genes and suggest its disruption underlies developmental disorders such as KBG syndrome.