The Disordered Region of ASXL1 Acts as an Auto‐Regulator Through Condensation

ABSTRACT Intrinsically disordered regions (IDRs) are common in chromatin regulators, yet how their sequence encodes regulatory logic remains unclear. Here, we show that the long linker IDR of ASXL1 (Additional Sex Combs Like 1) functions as an embedded autoregulatory module. A basic condensation‐prone segment is suppressed by a downstream acidic “charge block,” forming an electrostatic switch that gates condensation. Disease‐associated truncations remove this inhibition, unleashing phase separation and recruiting BRD2 (Bromodomain‐containing protein 2) to ectopic chromatin loci. Distinct truncation sites yield graded effects on condensate formation, chromatin accessibility, and neutrophil differentiation. Charge‐reversing mutations restore liquid‐liquid phase separation (LLPS) in a sequence‐dependent manner. Proteomic and imaging analyses identify BRD2 as a key condensate‐integrated factor whose mislocalization alters chromatin state. A compound screen reveals that Tosedostat reduces C‐terminally truncated ASXL1 (ASXL1‐TR) condensation and partially restores nuclear segmentation. Together, these findings define a tunable electrostatic switch within a long IDR and establish a broader model in which autoregulatory IDRs orchestrate condensation, chromatin engagement, and lineage fidelity.