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 B.A. Roy; Christian Babbs; Bart Ghesquiere; James Davies; Andrew J.M. Howden; Linda V. Sinclair; Jim R. Hughes; Mira Kassouf; Rob Beagrie; Douglas R. Higgs; Hal Drakesmith

doi:10.1038/s41467-025-57683-z

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

Alexandra E. Preston (Lead / Corresponding author), Joe N. Frost, Megan R. Teh, Mohsin Badat, Andrew E. Armitage, Ruggiero Norfo, Sarah K. Wideman, Muhammad Hanifi, Natasha White, Noémi B.A. Roy, Christian Babbs, Bart Ghesquiere, James Davies, Andrew J.M. Howden, Linda V. Sinclair, Jim R. Hughes, Mira Kassouf, Rob Beagrie, Douglas R. Higgs (Lead / Corresponding author), Hal Drakesmith (Lead / Corresponding author)

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

9 Downloads (Pure)

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.

Original language	English
Article number	2749
Number of pages	15
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	24 Mar 2025
DOIs	https://doi.org/10.1038/s41467-025-57683-z
Publication status	E-pub ahead of print - 24 Mar 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-025-57683-zLicence: CC BY

Final published version
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.
Final published version, 1.92 MBLicence: CC BY

Cite this

Preston, A. E., Frost, J. N., Teh, M. R., Badat, M., Armitage, A. E., Norfo, R., Wideman, S. K., Hanifi, M., White, N., Roy, N. B. A., Babbs, C., Ghesquiere, B., Davies, J., Howden, A. J. M., Sinclair, L. V., Hughes, J. R., Kassouf, M., Beagrie, R., Higgs, D. R., & Drakesmith, H. (2025). Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis. Nature Communications, 16(1), Article 2749. Advance online publication. https://doi.org/10.1038/s41467-025-57683-z

@article{6928e2505aac413d9859648d0f268e62,

title = "Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis",

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.",

author = "Preston, \{Alexandra E.\} and Frost, \{Joe N.\} and Teh, \{Megan R.\} and Mohsin Badat and Armitage, \{Andrew E.\} and Ruggiero Norfo and Wideman, \{Sarah K.\} and Muhammad Hanifi and Natasha White and Roy, \{No{\'e}mi B.A.\} and Christian Babbs and Bart Ghesquiere and James Davies and Howden, \{Andrew J.M.\} and Sinclair, \{Linda V.\} and Hughes, \{Jim R.\} and Mira Kassouf and Rob Beagrie and Higgs, \{Douglas R.\} and Hal Drakesmith",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = mar,

day = "24",

doi = "10.1038/s41467-025-57683-z",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Preston, AE, Frost, JN, Teh, MR, Badat, M, Armitage, AE, Norfo, R, Wideman, SK, Hanifi, M, White, N, Roy, NBA, Babbs, C, Ghesquiere, B, Davies, J, Howden, AJM, Sinclair, LV, Hughes, JR, Kassouf, M, Beagrie, R, Higgs, DR & Drakesmith, H 2025, 'Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis', Nature Communications, vol. 16, no. 1, 2749. https://doi.org/10.1038/s41467-025-57683-z

TY - JOUR

T1 - Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis

AU - Preston, Alexandra E.

AU - Frost, Joe N.

AU - Teh, Megan R.

AU - Badat, Mohsin

AU - Armitage, Andrew E.

AU - Norfo, Ruggiero

AU - Wideman, Sarah K.

AU - Hanifi, Muhammad

AU - White, Natasha

AU - Roy, Noémi B.A.

AU - Babbs, Christian

AU - Ghesquiere, Bart

AU - Davies, James

AU - Howden, Andrew J.M.

AU - Sinclair, Linda V.

AU - Hughes, Jim R.

AU - Kassouf, Mira

AU - Beagrie, Rob

AU - Higgs, Douglas R.

AU - Drakesmith, Hal

PY - 2025/3/24

Y1 - 2025/3/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=105000632581&partnerID=8YFLogxK

U2 - 10.1038/s41467-025-57683-z

DO - 10.1038/s41467-025-57683-z

M3 - Article

C2 - 40128524

AN - SCOPUS:105000632581

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2749

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this