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

Lenz, Jonathan ; Liefke, Robert ; Funk, Julianne ; Shoup, Samuel ; Nist, Andrea ; Stiewe, Thorsten ; Schulz, Robert; Tokusumi, Yumiko; Albert, Lea ; Raifer, Hartmann; Förstemann, Klaus ; Vazquez, Olalla; Tokusumi, Tsuyoshi; Fossett, Nancy und Brehm, Alexander (2021): Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis.
In: PLOS Genetics 17(2), e1009318

Abstract

The generation of lineage-specific gene expression programmes that alter proliferation capacity, metabolic profile and cell type-specific functions during differentiation from multipotent stem cells to specialised cell types is crucial for development. During differentiation gene expression programmes are dynamically modulated by a complex interplay between sequence-specific transcription factors, associated cofactors and epigenetic regulators. Here, we study U-shaped (Ush), a multi-zinc finger protein that maintains the multipotency of stem cell-like hemocyte progenitors during Drosophila hematopoiesis. Using genomewide approaches we reveal that Ush binds to promoters and enhancers and that it controls the expression of three gene classes that encode proteins relevant to stem cell-like functions and differentiation: cell cycle regulators, key metabolic enzymes and proteins conferring specific functions of differentiated hemocytes. We employ complementary biochemical approaches to characterise the molecular mechanisms of Ush-mediated gene regulation. We uncover distinct Ush isoforms one of which binds the Nucleosome Remodeling and Deacetylation (NuRD) complex using an evolutionary conserved peptide motif. Remarkably, the Ush/NuRD complex specifically contributes to the repression of lineage-specific genes but does not impact the expression of cell cycle regulators or metabolic genes. This reveals a mechanism that enables specific and concerted modulation of functionally related portions of a wider gene expression programme. Finally, we use genetic assays to demonstrate that Ush and NuRD regulate enhancer activity during hemocyte differentiation in vivo and that both cooperate to suppress the differentiation of lamellocytes, a highly specialised blood cell type. Our findings reveal that Ush coordinates proliferation, metabolism and cell type-specific activities by isoform-specific cooperation with an epigenetic regulator.

Author summary: In multicellular organisms common progenitors differentiate into various kinds of specialised cells. During differentiation metabolic profiles and proliferation potentials are progressively adjusted and cell type-specific traits are established by the coordinated activation and inactivation of genes. Here we study U-shaped (Ush), a conserved gene regulator that acts during macrophage differentiation in Drosophila melanogaster. We uncover that Ush coordinates the activation and inactivation of three differentiation-related gene groups, thereby modulating lipid metabolism, promoting cell division and maintaining a progenitor state. These functions are conferred by different Ush protein isoforms and their associated co-factors. One such co-factor, the nucleosome remodeling and deacetylation complex dNuRD, contributes to progenitor state maintenance but is not required for other Ush-regulated processes. This exemplifies how a single gene regulator can simultaneously influence different aspects of cellular differentiation by employing protein isoforms and isoform-specific co-regulator interactions.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1553-7404
• Sprache: Englisch