HomeENGLISH MAGAZINESleight of hand: HIF actor pulls fetal globin from the sickling without...

Sleight of hand: HIF actor pulls fetal globin from the sickling without using other FINGERs

Hemoglobin is like a protein sponge that soaks up oxygen and allows red blood cells to ferry it throughout the body. Adult hemoglobin contains four protein subunits – two alpha-globin and two beta-globin. Mutations in the latter cause sickle cell disease and beta-thalassemia. But humans have another hemoglobin subunit gene (gamma-globin), which is expressed instead of beta-globin during fetal development. Gamma-globin combines with alpha-globin to form HbF. Normally around birth, gamma-globin expression is turned off and beta-globin is turned on, resulting in a switch from fetal hemoglobin (HbF) to adult hemoglobin. Scientists at St. Jude Children’s Research Hospital led by professor Weiss have shown how a protein responsible for adapting to low oxygen conditions, causes increased expression of HbF in adults. The finding has implications for treating sickle cell disease and beta-thalassemia, serious blood disorders that affect millions of individuals. The research was published today in the well-known journal Nature.

Previous works of the Weiss lab has demonstrated that other transcription factors, instead, work as fetal globin gene repressors. Although lineage-restricted transcription factors such as GATA1 and TAL1 are essential for erythroid-specific transcription of the globin genes, BCL11A and ZBTB7A play a dominant role in the fetal-to-adult switch in globin gene transcription. Both of these factors bind at several locations along the β-globin gene cluster, including the promoter and upstream regions of the γ-globin genes, to silence γ-globin transcription. Then another zinc finger nuclear factor like ZNF410 was very recently proven to suppress gamma globin gene expression. Little is known about this transcription factor: it is only known to be is widely expressed across human tissues and in blood ZNF410 is highly expressed in the erythroid lineage. Dr Weiss and his coworkers demonstrated that ZNF410 that genetic depletion of his gene in immature erythrocytes raises gamma-globin gene expression and repressed, instead, the beta-globin protein.

Now the St. Jude group discovered that hypoxia inducible factor 1 (HIF1) directly promotes transcription of the gamma-globin gene to enhance HbF production. HIF1 is an important component of cells’ ability to sense and adapt to hypoxic conditions. In low oxygen conditions, HIF1 accumulates in many tissues and activates hundreds of genes, including HbF in red blood cells. Scientist in the Weiss lab showed that a drug that activates part of the cellular hypoxia response inhibits sickling of red blood cells derived from adults with sickle cell disease. The drug, a proline hydroxylase inhibitor, caused HIF1 to accumulate, bind a DNA regulatory region near the gamma globin gene, activating its transcription to produce HbF and inhibit cell ‘sickling.’ Proline hydroxylase inhibitors are currently in late stage clinical development for the treatment of anemia associated with chronic kidney disease. These drugs work by stabilizing HIF proteins to stimulate the production of erythropoietin, a hormone that drives red blood cell production.

Mitchell J. Weiss, MD, PhD., Chair at St. Jude Hematology Department Chair, explained thoroughly: “We have known for many years that persistent HbF expression after birth can alleviate the symptoms of sickle cell disease and beta-thalassemia. And very high HbF levels can cure these diseases, despite the defective beta-globin genes being present. Therefore, many laboratories are focused on understanding the perinatal switch from gamma- to beta-globin gene expression and figuring out new ways to reverse it with drugs or genetic therapies. Our findings indicate that proline hydroxylase inhibitors might be useful for treatment of sickle cell disease or beta-thalassemia, where turning on HbF production has therapeutic benefits. Approximately 20% of adult sickle cell disease patients develop kidney failure with related anemia. Proline hydroxylase inhibitors might serve a dual purpose in these individuals, by stimulating the production of both erythropoietin (EPO) and fetal hemoglobin (HbF)”.

“Our current study establishes a direct connection between this hypoxia adaptation and HbF expression. This connection explains longstanding clinical observations that HbF is induced during accelerated production of red blood cells after exposure to hypoxia or in some forms of anemia, conditions termed “stress erythropoiesis”. Identification of gamma-globin as a HIF target gene supports the notion that HbF evolved as a protective mechanism against hypoxia. The Nobel Prize in Physiology or Medicine was awarded to the discovery of the HIF pathway in 2019. Studies of hemoglobin over more than 50 years have established many general principles in biology and medicine. It is exciting and gratifying that investigations into hemoglobin and globin gene expression continue to produce new, clinically relevant discoveries”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Feng R, Mayuranathan T et al. Nature. 2022 Oct 12.

Qin K, Huang P et al. Nat Genet. 2022; 54(6):874-84.

Doerfler PA et al. Nature Genet. 2021; 53(8):1177-86.

Ludwig LS, Lareau CA et al Cell Rep 2019; 27:3228.

Martyn GE et al. Nature Genet. 2018; 50:498–503.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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