Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis
Red blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis.
Authors
- Muhammad Hanifi
- Natasha White (ORCID: https://orcid.org/0000-0001-5793-892X)
- Megan R. Teh (ORCID: https://orcid.org/0000-0002-8095-9961)
- Douglas R. Higgs (ORCID: https://orcid.org/0000-0003-3579-8705)
- James O. J. Davies (ORCID: https://orcid.org/0000-0002-4108-4357)
- Andrew E. Armitage (ORCID: https://orcid.org/0000-0001-5977-6602)
- Mira T. Kassouf (ORCID: https://orcid.org/0000-0002-9781-921X)
- Bart Ghesquière (ORCID: https://orcid.org/0000-0003-1547-1705)
- Ruggiero Norfo (ORCID: https://orcid.org/0000-0002-9485-6285)
- Joe N. Frost (ORCID: https://orcid.org/0000-0002-5946-6062)
- Hal Drakesmith (ORCID: https://orcid.org/0000-0002-8503-6103)
- Robert A. Beagrie (ORCID: https://orcid.org/0000-0003-1076-5595)
- Jim R. Hughes (ORCID: https://orcid.org/0000-0002-8955-7256)
- Andrew J.M. Howden (ORCID: https://orcid.org/0000-0002-4332-9469)
- Sarah K. Wideman (ORCID: https://orcid.org/0000-0001-7803-9894)
- Mohsin Badat (ORCID: https://orcid.org/0000-0003-0744-5427)
- Christian Babbs (ORCID: https://orcid.org/0000-0002-1898-5878)
- Noémi Roy (ORCID: https://orcid.org/0000-0002-0919-0790)
- Alexandra E. Preston (ORCID: https://orcid.org/0000-0003-0008-5916)
- Linda V. Sinclair (ORCID: https://orcid.org/0000-0003-1248-7189)
Institutions
- University of Modena and Reggio Emilia (IT)
- Memorial Sloan Kettering Cancer Center (US)
- Centre for Human Genetics (GB)
- Queen Mary University of London (GB)
- University of Dundee (GB)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- John Radcliffe Hospital (GB)
- National Institute for Health and Care Research (GB)
- University of Oxford (GB)
- VIB-KU Leuven Center for Cancer Biology (BE)
- MRC Weatherall Institute of Molecular Medicine (GB)
- MRC Human Immunology Unit (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-24
- DOI
- https://doi.org/10.1038/s41467-025-57683-z
- Citations
- 3
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 4.88
Funders
- Medical Research Foundation