Autoinhibition of ASXL1 Condensation via Opposing-Charge Blocks in Its Disordered Region

Long intrinsically disordered regions (IDRs) are prevalent in chromatin regulators, yet how they encode regulatory logic remains unclear. Here, we show that ASXL1, a frequently mutated scaffold protein in myeloid malignancies, employs a charge-based autoregulatory mechanism to control phase separation. Truncations within ASXL1’s long linker IDR (llIDR) remove a negatively charged segment that normally inhibits condensate formation by electrostatically masking the positively charged ASXM1 domain. Loss of this charge block shifts ASXL1 into a condensate-competent state, promoting liquid-like assembly and facilitating recruitment of the chromatin reader BRD2. These aberrant condensates alter BRD2’s genomic localization, disrupt heterochromatin organization, and impair neutrophil differentiation. Pharmacological disruption of condensates partially restores nuclear morphology, suggesting therapeutic tractability. Our findings define a tunable electrostatic switch within ASXL1’s IDR and provide a general framework for understanding how charge patterning in IDRs governs nuclear condensation and lineage fidelity.