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NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBP? and inflammatory signaling.

ABSTRACT: Members of the NR4A subfamily of nuclear receptors have complex, overlapping roles during hematopoietic cell development and also function as tumor suppressors of hematologic malignancies. We previously identified NR4A1 and NR4A3 (NR4A1/3) as functionally redundant suppressors of acute myeloid leukemia (AML) development. However, their role in hematopoietic stem cell (HSC) homeostasis remains to be disclosed. Using a conditional Nr4a1/Nr4a3 knockout mouse (CDKO), we show that codepletion of NR4A1/3 promotes acute changes in HSC homeostasis including loss of HSC quiescence, accumulation of oxidative stress, and DNA damage while maintaining stem cell regenerative and differentiation capacity. Molecular profiling of CDKO HSCs revealed widespread upregulation of genetic programs governing cell cycle and inflammation and an aberrant activation of the interferon and NF-?B signaling pathways in the absence of stimuli. Mechanistically, we demonstrate that NR4A1/3 restrict HSC proliferation in part through activation of a C/EBP?-driven antiproliferative network by directly binding to a hematopoietic-specific Cebpa enhancer and activating Cebpa transcription. In addition, NR4A1/3 occupy the regulatory regions of NF-?B-regulated inflammatory cytokines, antagonizing the activation of NF-?B signaling. Taken together, our results reveal a novel coordinate control of HSC quiescence by NR4A1/3 through direct activation of C/EBP? and suppression of activation of NF-?B-driven proliferative inflammatory responses.

SUBMITTER: Freire PR

PROVIDER: S-EPMC5863701 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling.

Freire Pablo R PR Conneely Orla M OM

Blood 20180117 10

Members of the NR4A subfamily of nuclear receptors have complex, overlapping roles during hematopoietic cell development and also function as tumor suppressors of hematologic malignancies. We previously identified NR4A1 and NR4A3 (NR4A1/3) as functionally redundant suppressors of acute myeloid leukemia (AML) development. However, their role in hematopoietic stem cell (HSC) homeostasis remains to be disclosed. Using a conditional <i>Nr4a1</i>/<i>Nr4a3</i> knockout mouse (CDKO), we show that codep ...[more]

PMID: 29343483

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Project description:BackgroundBy studying genome-wide expression patterns in healthy and diseased tissues across a wide range of pathophysiological conditions, DNA microarrays have revealed unique insights into complex diseases. However, the high-dimensionality of microarray data makes interpretation of heterogeneous gene expression studies inherently difficult.ResultsUsing a large-scale analysis of more than 40 microarray studies encompassing ~2400 mammalian tissue samples, we identified a common theme across heterogeneous microarray studies evident by a robust genome-wide inverse regulation of metabolic and cell signaling pathways: We found that upregulation of cell signaling pathways was invariably accompanied by downregulation of cell metabolic transcriptional activity (and vice versa). Several findings suggest that this characteristic gene expression pattern represents a new principle of mammalian transcriptional regulation. First, this coordinated transcriptional pattern occurred in a wide variety of physiological and pathophysiological conditions and was identified across all 20 human and animal tissue types examined. Second, the differences in metabolic gene expression predicted the magnitude of differences for signaling and all other pathways, i.e. tissue samples with similar expression levels of metabolic transcripts did not show any differences in gene expression for all other pathways. Third, this transcriptional pattern predicted a profound effect on the proteome, evident by differences in structure, stability and post-translational modifications of proteins belonging to signaling and metabolic pathways, respectively.ConclusionsOur data suggest that in a wide range of physiological and pathophysiological conditions, gene expression changes exhibit a recurring pattern along a transcriptional axis, characterized by an inverse regulation of major metabolic and cell signaling pathways. Given its widespread occurrence and its predicted effects on protein structure, protein stability and post-translational modifications, we propose a new principle for transcriptional regulation in mammalian biology.

Dataset Information

NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBP? and inflammatory signaling.

Publications

NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling.

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