Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis

Alexandra E. Preston (), Joe N. Frost, Megan R. Teh, Mohsin Badat, Andrew E. Armitage, Ruggiero Norfo, Sarah K. Wideman, Muhammad Hanifi, Natasha White, Noémi BA. Roy, Christian Babbs, Bart Ghesquiere, James Davies, Andrew JM. Howden, Linda V. Sinclair, Jim R. Hughes, Mira Kassouf, Rob Beagrie (), Douglas R. Higgs and Hal Drakesmith ()
Additional contact information
Alexandra E. Preston: University of Oxford
Joe N. Frost: University of Oxford
Megan R. Teh: University of Oxford
Mohsin Badat: University of Oxford
Andrew E. Armitage: University of Oxford
Ruggiero Norfo: University of Oxford
Sarah K. Wideman: University of Oxford
Muhammad Hanifi: University of Oxford
Natasha White: University of Oxford
Noémi BA. Roy: University of Oxford
Christian Babbs: University of Oxford
Bart Ghesquiere: Katholieke Universiteit Leuven
James Davies: University of Oxford
Andrew JM. Howden: University of Dundee
Linda V. Sinclair: University of Dundee
Jim R. Hughes: University of Oxford
Mira Kassouf: University of Oxford
Rob Beagrie: University of Oxford
Douglas R. Higgs: University of Oxford
Hal Drakesmith: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57683-z

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