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A new study, published in Nature Communications, found that two seemingly unrelated genes (Nprl3 and alpha-globin) that have been neighbours for over 500 million years, share enhancers for joint control of metabolism and red blood cell development (known as erythropoiesis). This provides a functional explanation for the deep-time co-conservation of these genes, and advances understanding of the complex process by which red blood cells develop from their precursor cells to carry out their essential oxygen-carrying role.
In erythropoiesis, precursor cells undergo changes in metabolism and gene expression to degrade organelles and favour production of the oxygen-carrying protein haemoglobin. Preston et al approached erythropoiesis from a metabolic perspective, and used transgenic animal models developed over several years by the Higgs Group to study alpha-globin (a sub-unit of haemoglobin).
Expression of alpha-globin is highly upregulated during erythropoiesis. Most of the enhancers responsible for this are found within a neighbouring gene called Nprl3, which serves a key role in cell metabolism. The Nprl3 and alpha-globin genes have been genomically adjacent for over half a billion years (back to jawless vertebrates).
The research team, led by Dr Alexandra Preston, showed that these erythroid-specific enhancers are also responsible for the upregulation of Nprl3 in erythroid cells, and that Nprl3’s metabolic function is critical for erythropoiesis. When Nprl3 expression is too low, red blood cell precursors cannot adapt their metabolic state in response to fluctuations in amino acids, iron, or erythropoietin, glycolysis goes awry, and red blood cell production is stalled. Thus, two genes of seemingly unrelated function share enhancers for joint control of metabolism and erythrocyte development, providing a functional explanation for their deep-time co-conservation.
Professor Hal Drakesmith, one of the lead authors, said:
This study provides a new concept for a wider role of the alpha-globin locus that incorporates metabolic regulation to ensure optimal haemoglobin synthesis and erythropoietic output.
Read the full paper here: https://www.nature.com/articles/s41467-025-57683-z