Factors with Dual Roles as Activators and Repressors Regulate Intermediate Expression Levels

Precise control of gene expression levels is essential for normal cell functions, yet how they are defined and tightly maintained, particularly at intermediate levels, remains elusive. Here, using a series of new sequencing, imaging, and functional assays, we uncover a class of transcription factors, referred to as dual TFs, which reduce high expression but increase low expression to achieve stable intermediate levels. Dual TFs directly exert activating and repressing functions via condensate-forming domains that compartmentalize core transcriptional unit selectively. Clinically relevant mutations in these domains, which are linked to a range of developmental disorders, impair condensate selectivity and dual TF activity. These results collectively address a fundamental question in expression regulation and demonstrate the potential of dual TFs as powerful effectors for engineering controlled expression levels. Overall design: ACC-seq to capture differential chromatin accessibility features in response to modulations of condensate occupancy of mESC (R1 strain)