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EGR1 is a gatekeeper of inflammatory enhancers in human macrophages.

ABSTRACT: Monocytes and monocyte-derived macrophages originate through a multistep differentiation process. First, hematopoietic stem cells generate lineage-restricted progenitors that eventually develop into peripheral, postmitotic monocytes. Second, blood-circulating monocytes undergo differentiation into macrophages, which are specialized phagocytic cells capable of tissue infiltration. While monocytes mediate some level of inflammation and cell toxicity, macrophages boast the widest set of defense mechanisms against pathogens and elicit robust inflammatory responses. Here, we analyze the molecular determinants of monocytic and macrophagic commitment by profiling the EGR1 transcription factor. EGR1 is essential for monopoiesis and binds enhancers that regulate monocytic developmental genes such as CSF1R However, differentiating macrophages present a very different EGR1 binding pattern. We identify novel binding sites of EGR1 at a large set of inflammatory enhancers, even in the absence of its binding motif. We show that EGR1 repressive activity results in suppression of inflammatory genes and is mediated by the NuRD corepressor complex.

SUBMITTER: Trizzino M

PROVIDER: S-EPMC7806227 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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EGR1 is a gatekeeper of inflammatory enhancers in human macrophages.

Trizzino Marco M Zucco Avery A Deliard Sandra S Wang Fang F Barbieri Elisa E Veglia Filippo F Gabrilovich Dmitry D Gardini Alessandro A

Science advances 20210113 3

Monocytes and monocyte-derived macrophages originate through a multistep differentiation process. First, hematopoietic stem cells generate lineage-restricted progenitors that eventually develop into peripheral, postmitotic monocytes. Second, blood-circulating monocytes undergo differentiation into macrophages, which are specialized phagocytic cells capable of tissue infiltration. While monocytes mediate some level of inflammation and cell toxicity, macrophages boast the widest set of defense mec ...[more]

PMID: 33523892

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Project description:BackgroundDuring aging, hematopoietic stem cells (HSC) lose progressively both their self-renewal and differentiation potential. The precise molecular mechanisms of this phenomenon are not well established. To uncover the molecular events underlying this event, we have performed a bioinformatics analysis of 650 single-cell transcriptomes.MethodsSingle-cell transcriptome analyses of expression heterogeneity, cell cycle, and cell trajectory in human cell compartment enriched in hematopoietic stem cell compartment were investigated in the bone marrow according to the age of the donors. Identification of aging-related nodules was identified by weighted correlation network analysis in this primitive compartment.ResultsThe analysis of single-cell transcriptomes allowed to uncover a major upregulation of EGR1 in human-aged lineage-CD34+CD38- cells which present cell cycle dysregulation with reduction of G2/M phase according to less expression of CCND2 during S phase. EGR1 upregulation in aging hematopoietic stem cells was found to be independent of cell cycle phases and gender. EGR1 expression trajectory in aged HSC highlighted a signature enriched in hematopoietic and immune disorders with the best induction of AP-1 complex and quiescence regulators such as EGR1, BTG2, JUNB, and NR41A. Sonic Hedgehog-related TMEM107 transmembrane molecule followed also EGR1 cell trajectory. EGR1-dependent gene weighted network analysis in human HSC-associated IER2 target protein-specific regulators of PP2A activity, IL1B, TNFSF10 ligands, and CD69, SELP membrane molecules in old HSC module with immune and leukemogenic signature. In contrast, for young HSC which were found with different cell cycle phase progression, its specific module highlighted upregulation of HIF1A hypoxic factor, PDE4B immune marker, DRAK2 (STK17B) T cell apoptosis regulator, and MYADM myeloid-associated marker.ConclusionEGR1 was found to be connected to the aging of human HSC and highlighted a specific cell trajectory contributing to the dysregulation of an inflammatory and leukemia-related transcriptional program in aged human HSCs. EGR1 and its program were found to be connected to the aging of human HSC with dissociation of quiescence property and cell cycle phase progression in this primitive hematopoietic compartment.

Dataset Information

EGR1 is a gatekeeper of inflammatory enhancers in human macrophages.

Publications

EGR1 is a gatekeeper of inflammatory enhancers in human macrophages.

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