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

• Published in: Nature communications Vol. 10; no. 1; p. 1072
• Main Authors: Kidoya, Hiroyasu, Muramatsu, Fumitaka, Shimamura, Teppei, Jia, Weizhen, Satoh, Takashi, Hayashi, Yumiko, Naito, Hisamichi, Kunisaki, Yuya, Arai, Fumio, Seki, Masahide, Suzuki, Yutaka, Osawa, Tsuyoshi, Akira, Shizuo, Takakura, Nobuyuki
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 06.03.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Bone marrow; Bone Marrow - pathology; Cell Differentiation - genetics; Cell Line, Tumor; Cell Proliferation - genetics; Cell Self Renewal - genetics; Cell self-renewal; Cells (biology); Datasets as Topic; GATA2 Transcription Factor - genetics; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene regulation; HEK293 Cells; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - physiology; Homeostasis; Humans; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Mice, Inbred C57BL; Mice, Knockout; Post-transcription; Progenitor cells; Prognosis; Proteins; Ribonuclease; Ribonucleases - genetics; Ribonucleases - metabolism; RNA Processing, Post-Transcriptional - physiology; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Stem cells; T-Cell Acute Lymphocytic Leukemia Protein 1 - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Transplantation Chimera; Tumor suppressor genes; Zinc; Zinc finger proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09028-w

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.