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<p>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. <i>Nprl3</i> (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for &gt;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月24日

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  • 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,
  • Hal Drakesmith

摘要

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.