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

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.

SUBMITTER: Lenz J

PROVIDER: S-EPMC7891773 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Lenz Jonathan J Liefke Robert R Funk Julianne J Shoup Samuel S Nist Andrea A Stiewe Thorsten T Schulz Robert R Tokusumi Yumiko Y Albert Lea L Raifer Hartmann H Förstemann Klaus K Vázquez Olalla O Tokusumi Tsuyoshi T Fossett Nancy N Brehm Alexander A

PLoS genetics 20210218 2

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 ...[more]

PMID: 33600407

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Project description:The generation and modulation of lineage-specific gene expression programmes that determine proliferation capacity, metabolic profile and cell type-specific activities at each stage of differentiation are crucial for metazoan development. Gene expression programmes are moulded by a complex interplay between sequence-specific transcription factors, cofactors and epigenetic regulators. Here, we study U-shaped (Ush), a genetically defined transcriptional cofactor that cooperates with GATA transcription factors during blood cell differentiation in Drosophila. We use a cell line that is derived from macrophage precursors to comprehensively analyse Ush function at the cellular level. Using genomewide approaches we reveal that Ush binds to thousands of promoters and enhancers that are enriched for GATA sites and that it is a major regulator of transcription. Ush controls the expression of at least three functionally distinct gene classes encoding proteins relevant to different aspects of macrophage differentiation: cell cycle regulators, key metabolic enzymes and proteins enabling macrophage-specific functions. Ush is essential to maintain proliferative capacity and coordinately regulates fatty acid degradation and synthesis. We employ complementary biochemical approaches to characterise the molecular mechanisms of Ush-mediated gene regulation. We uncover the existence of two major Ush isoforms. One of these, Ush-B, uses a short peptide sequence to bind the Nucleosome Remodeling and Deacetylation (NuRD) complex. We demonstrate that this mode of interaction is conserved between vertebrates and invertebrates. Remarkably, Ush-B/NuRD specifically contributes to the repression of macrophage-specific genes demonstrating that Ush isoforms and epigenetic regulators make differential contributions to Ush controlled transcription programmes. Finally, we use genetic methods to define Ush and NuRD function in the developing fly. Ush and NuRD regulate enhancer activity during macrophage differentiation and both cooperate to suppress the formation of lamellocytes. Our findings uncover how a transcriptional cofactor can coordinate distinct cellular activities (proliferation, metabolism and cell type-specific functions) that are relevant for differentiation and maintenance of cell type-specific phenotypes.

Dataset Information

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

Publications

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

Similar Datasets

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