Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis
Autoři:
Jonathan Lenz aff001; Robert Liefke aff001; Julianne Funk aff003; Samuel Shoup aff001; Andrea Nist aff004; Thorsten Stiewe aff004; Robert Schulz aff005; Yumiko Tokusumi aff005; Lea Albert aff006; Hartmann Raifer aff007; Klaus Förstemann aff008; Olalla Vázquez aff006; Tsuyoshi Tokusumi aff005; Nancy Fossett aff009; Alexander Brehm aff001
Působiště autorů:
Institute of Molecular Biology and Tumor Research, Biomedical Research Center, Philipps-University, Marburg, Germany
aff001; Department of Hematology, Oncology and Immunology, University Hospital Giessen and Marburg, Marburg, Germany
aff002; Institute of Molecular Oncology, Philipps-University, Marburg, Germany
aff003; Genomics Core Facility, Institute of Molecular Oncology, Member of the German Center for Lung Research (DZL), Philipps-University, Marburg, Germany
aff004; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
aff005; Faculty of Chemistry, Philipps-University, Marburg, Germany
aff006; Flow Cytometry Core Facility, Institute for Medical Microbiology and Hospital Hygiene, Biomedical Research Center, Philipps-University, Marburg, Germany
aff007; Gene Center and Dept. of Biochemistry, Ludwig-Maximilians-Universität, München, Germany
aff008; Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
aff009
Vyšlo v časopise:
Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis. PLoS Genet 17(2): e1009318. doi:10.1371/journal.pgen.1009318
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009318
Souhrn
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.
Klíčová slova:
Cell cycle and cell division – Cell differentiation – Drosophila melanogaster – Gene expression – Gene regulation – Hemocytes – Invertebrate genomics – Transcriptional control
Zdroje
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