Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis

Hiroyasu Kidoya,Takashi Satoh,Nobuyuki Takakura,Hisamichi Naito,Fumio Arai,Yuya Kunisaki,Yumiko Hayashi,Tsuyoshi Osawa,Teppei Shimamura,Yutaka Suzuki,Fumitaka Muramatsu,Masahide Seki,Weizhen Jia,Shizuo Akira

doi:10.1038/s41467-019-09028-w

Abstract

The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. HSPC fate is controlled by signals from the bone marrow niche resulting in alteration of the stem cell transcription network. Regnase-1, a member of the CCCH zinc finger protein family possessing RNAse activity, mediates post-transcriptional regulatory activity through degradation of target mRNAs. The precise function of Regnase-1 has been explored in inflammation-related cytokine expression but its function in hematopoiesis has not been elucidated. Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA. In addition, we found that dysfunction of Regnase-1 leads to the rapid onset of abnormal hematopoiesis. Thus, our data reveal that Regnase-1-mediated post-transcriptional regulation is required for HSPC maintenance and suggest that it represents a leukemia tumor suppressor.

Highlights

The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder
The expression of multiple genes was different in HSPCs from adult bone marrow (BM) and E14.5 fetal liver (FL)
We found that Regnase-1 was relatively highly expressed in all HSPC subsets compared to the whole population of lineage-committed cells and differentiated progenitor cells (Fig. 1c, Supplementary Fig. 1a)

Summary

Introduction

The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. Various key transcription factors involved in HSPC homeostasis have been identified, regulatory mechanisms controlling the transcriptional network regulating hematopoiesis remain undetermined. The CCCH zinc finger protein Regnase-1 encoded by the ZC3H12A (MCPIP1) gene has been identified as a ribonuclease that suppresses gene expression through degradation of transcripts[13,14] This protein acts as a negative regulator of inflammatory responses by destabilizing inflammation-related cytokines and transcription factor mRNAs such as interleukin-1β (IL-1β), IL-2, IL-6, IL-12p40, and c-Rel[13,14,15,16]. In addition to its immune response functions, Regnase-1 is involved in a wide variety of biological processes such as brain development and adipogenesis by controlling cell differentiation and apoptosis[18,19]

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Results

Conclusion