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

Pablo R. Freire and Orla M. Conneely

Key points

  • NR4A1/3 nuclear receptors suppress hyper-proliferation and DNA damage of HSCs

  • NR4A1/3 act as transcriptional activators of C/EBPα while repressing a proliferative inflammatory response in HSCs.

Abstract

Members of the NR4A subfamily of nuclear receptors have complex, overlapping roles during hematopoietic cell development and also function as tumor suppressors of hematological malignancies. We previously identified NR4A1 and NR4A3 as functionally redundant suppressors of 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 up-regulation of genetic programs governing cell cycle and inflammation and an aberrant activation of the interferon and NF-κB signaling pathways in the absence of stimuli. Mechanistically, we demonstrate that NR4A1/3 restrict HSC proliferation in part through activation of a C/EBPα-driven anti-proliferative network by directly binding to a hematopoietic-specific Cebpa enhancer and activating Cebpa transcription. Additionally, NR4A1/3 occupy the regulatory regions of NF-κB-regulated inflammatory cytokines, antagonizing the activation of NF-κB signaling. Taken together, our results reveal a novel coordinate control of HSC quiescence by NR4A1/3 through direct activation of C/EBPα and suppression of activation of NF-κB- driven proliferative inflammatory responses.

  • Submitted July 11, 2017.
  • Accepted January 8, 2018.