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Notch1 expression is regulated at the post-transcriptional level by the 3′ untranslated region in hematopoietic stem cell development

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Abstract

In hematopoiesis, the expression of critical genes is regulated in a stage-specific manner to maintain normal hematopoiesis. Notch1 is an essential gene involved in the commitment and development of the T-cell lineage. However, the regulation of Notch1 in hematopoiesis is controversial, particularly at the level of hematopoietic stem cell (HSC). Here, we found that the expression of Notch1 is controlled at the post-transcriptional level in HSCs. HSCs express a considerable level of Notch1 mRNA, but its protein level is very low, suggesting a post-transcriptional suppression for Notch1. Using a retroviral sensor vector expressing a fusion mRNA of GFP and 3′ untranslated region (3′UTR) of a target gene, we demonstrated that the Notch1-3′UTR had a post-translational suppressive effect only at the HSC but not in the downstream progenitor stages. The sequence motif AUnA was required for this post-transcriptional regulation by the Notch1-3′UTR. Interestingly, this Notch1-3′UTR-mediated suppressive effect was relieved when HSCs were placed in the thymus, but not in the bone marrow. Thus, the expression of Notch1 in HSCs is regulated by microenvironment at the post-transcriptional level, which may control T lymphoid lineage commitment from HSCs.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health (NIH) (DK050654, DK061320, and CA072009) and by a grant-in-aid for Scientific Research (B) (#22390196) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan

    Shinichi Mizuno, Tadafumi Iino & Koichi Akashi

  2. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Yong Chong & Koichi Akashi

  3. Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan

    Yojiro Arinobu & Koichi Akashi

  4. Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan

    Hidetoshi Ozawa

  5. Department of Cancer Immunology and AIDs, Dana-Farber Cancer Institute, Boston, USA

    Shinichi Mizuno, Tadafumi Iino, Hidetoshi Ozawa, Yojiro Arinobu, Yong Chong & Koichi Akashi

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  1. Shinichi Mizuno
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  2. Tadafumi Iino
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  3. Hidetoshi Ozawa
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  4. Yojiro Arinobu
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  5. Yong Chong
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  6. Koichi Akashi
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Correspondence to Koichi Akashi.

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Mizuno, S., Iino, T., Ozawa, H. et al. Notch1 expression is regulated at the post-transcriptional level by the 3′ untranslated region in hematopoietic stem cell development. Int J Hematol 107, 311–319 (2018). https://doi.org/10.1007/s12185-017-2358-2

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  • DOI: https://doi.org/10.1007/s12185-017-2358-2

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