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

Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis
PLoS Genet. 2021 Feb 18;17(2):e1009318. doi: 10.1371/journal.pgen.1009318. eCollection 2021 Feb.
Authors
Jonathan Lenz 1 , Robert Liefke 1 2 , Julianne Funk 3 , Samuel Shoup 1 , Andrea Nist 4 , Thorsten Stiewe 4 , Robert Schulz 5 , Yumiko Tokusumi 5 , Lea Albert 6 , Hartmann Raifer 7 , Klaus Förstemann 8 , Olalla Vázquez 6 , Tsuyoshi Tokusumi 5 , Nancy Fossett 9 , Alexander Brehm 1
Affiliations
1 Institute of Molecular Biology and Tumor Research, Biomedical Research Center, Philipps-University, Marburg, Germany.
2 Department of Hematology, Oncology and Immunology, University Hospital Giessen and Marburg, Marburg, Germany.
3 Institute of Molecular Oncology, Philipps-University, Marburg, Germany.
4 Genomics Core Facility, Institute of Molecular Oncology, Member of the German Center for Lung Research (DZL), Philipps-University, Marburg, Germany.
5 Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
6 Faculty of Chemistry, Philipps-University, Marburg, Germany.
7 Flow Cytometry Core Facility, Institute for Medical Microbiology and Hospital Hygiene, Biomedical Research Center, Philipps-University, Marburg, Germany.
8 Gene Center and Dept. of Biochemistry, Ludwig-Maximilians-Universität, München, Germany.
9 Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
PMID: 33600407
DOI: 10.1371/journal.pgen.1009318
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.

Conflict of interest statement
The authors have declared that no competing interests exist. Author Robert Schulz was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge.