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dc.contributor.authorLenz, Jonathan
dc.contributor.authorLiefke, Robert
dc.contributor.authorFunk, Julianne
dc.contributor.authorShoup, Samuel
dc.contributor.authorNist, Andrea
dc.contributor.authorStiewe, Thorsten
dc.contributor.authorSchulz, Robert
dc.contributor.authorTokusumi, Yumiko
dc.contributor.authorAlbert, Lea
dc.contributor.authorRaifer, Hartmann
dc.contributor.authorFörstemann, Klaus
dc.contributor.authorVázquez, Olalla
dc.contributor.authorTokusumi, Tsuyoshi
dc.contributor.authorFossett, Nancy
dc.contributor.authorBrehm, Alexander
dc.date.accessioned2021-03-16T12:40:14Z
dc.date.available2021-03-16T12:40:14Z
dc.date.issued2021-02-18
dc.identifier.urihttp://hdl.handle.net/10713/14969
dc.description.abstractThe 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.en_US
dc.description.urihttps://doi.org/10.1371/journal.pgen.1009318en_US
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.ispartofPLoS Geneticsen_US
dc.subject.meshHematopoiesis--geneticsen_US
dc.subject.meshHematopoiesis--physiologyen_US
dc.subject.meshDrosophilaen_US
dc.titleUsh regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesisen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.pgen.1009318
dc.identifier.pmid33600407
dc.source.volume17
dc.source.issue2
dc.source.beginpagee1009318
dc.source.endpage
dc.source.countryUnited States


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