Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis

The generation of lineage-specific gene expression programmes that alter proliferation, metabolism and cell type-specific functions is crucial for development. Gene expression is dynamically modulated by a complex interplay between transcription factors and epigenetic regulators. Here, we study U-shaped (Ush), a multi-zinc finger protein that maintains the multipotency of stem cell-like hemocyte progenitors. We reveal that Ush binds promoters and enhancers and controls the expression of three gene classes: cell cycle regulators, key metabolic enzymes and hemocyte-specific proteins. We uncover a Ush isoform that binds the Nucleosome Remodeling and Deacetylation (NuRD) complex using a conserved peptide motif. Remarkably, the Ush/NuRD complex specifically contributes to repression of lineage-specific genes but does not impact cell cycle or metabolic genes. This mechanism enables concerted modulation of functionally related portions of a wider gene expression programme. Finally, we demonstrate that Ush and NuRD regulate enhancer activity during hemocyte differentiation in vivo and that both cooperate to suppress the differentiation of lamellocytes. Our findings reveal that Ush coordinates proliferation, metabolism and cell type-specific activities by isoform-specific cooperation with an epigenetic regulator.