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

ABSTRACT: 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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE146382 | GEO | 2021/01/25

REPOSITORIES: GEO

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Project description:Chickarmane2008 - Stem cell lineage - NANOG GATA-6 switch In this work, a dynamical model of lineage determination based upon a minimal circuit, as discussed in PMID: 17215298 , which contains the Oct4/Sox2/Nanog core as well its interaction with a few other key genes is discussed. This model is described in the article: A computational model for understanding stem cell, trophectoderm and endoderm lineage determination. Chickarmane V, Peterson C PloS one. 2008, 3(10):e3478 Abstract: BACKGROUND: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4. METHODOLOGY/ PRINCIPAL FINDINGS: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6. CONCLUSIONS: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state. This model is hosted on BioModels Database and identified by: MODEL8389825246 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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

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