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

## TL;DR

The disordered region of ASXL1 acts as a self-regulating switch that controls condensation and chromatin organization, with disease-related mutations disrupting this balance.

## Contribution

The discovery of an electrostatic 'basic platform + acidic brake' mechanism in ASXL1's IDR that autoregulates condensation and chromatin engagement.

## Key findings

- Disease-associated truncations remove the acidic brake, leading to uncontrolled condensation and BRD2 recruitment.
- Charge-reversing mutations and Tosedostat treatment can modulate condensation and restore nuclear segmentation.
- Truncation sites affect condensate formation, chromatin accessibility, and neutrophil differentiation in a graded manner.

## 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.

ASXL1's long IDR encodes an electrostatic “basic platform + acidic brake” that autoregulates condensation. Truncation at a clinical hotspot lifts this brake, forming condensates that retarget BRD2, remodel local chromatin accessibility, and impair neutrophil maturation. Conversely, a long truncation containing AA718–918 retains the inhibitory segment and suppresses condensation. These results illustrate how charge‐patterned IDRs govern nuclear organization and lineage fidelity.