GATA3 differentially regulates the transcriptome via zinc finger 2-modulated phase separation.

Phase separation (PS) underlies gene control by transcription factors. However, little is known about whether and how DNA-binding domains (DBDs) regulate the PS for transcription factors to differentially regulate the transcriptome. The transcription factor GATA3, a master immune regulator, is frequently mutated in breast cancer. Here, we report that GATA3 undergoes DBD-modulated PS to mediate the formation of chromatin condensates. We show that the DBD regulates the GATA3 PS through its zinc finger 2 (ZnF2) domain, which provides positive charges for multivalent electrostatic interactions mainly via two arginine amino acids, R329 and R330. Compared with breast-cancer-associated GATA3 without ZnF2-defective mutations, breast cancer GATA3 with ZnF2-defective mutations causes aberrant ZnF2-modulated PS and condensate formation to remodel the differentially regulated transcriptome, resulting in a favorable prognosis for patients and reduced tumor growth in mice. Therefore, GATA3 demonstrates a principle of how a transcription factor differentially regulates the transcriptome via DBD-modulated PS.