The link between hypoxia and fetal hemoglobin

Scientists at St.
Jude Children's Research Hospital have shown how a protein responsible for adapting to a hypoxic environment (hypoxia) can lead to increased expression of hemoglobin (HbF) in adult
fetuses.
The findings have implications for the treatment of sickle cell disease and beta-thalassemia, two serious blood disorders that affect millions of people
.
The study was published today in Nature
.

Hemoglobin is like a protein sponge that absorbs oxygen and allows red blood cells to transport oxygen throughout the body
.
Adult hemoglobin contains four protein subunits - two-globulin and two globulins
.
Mutations in globulin can cause sickle cell disease and thalassemia
.
But humans have another hemoglobin subgene (γ-globulin) that replaces β-globulin expression
during fetal development.
γ-globulin binds to α-globulin to form HbF
.
Usually around birth, γ-globulin expression is turned off and β-globulin is turned on, resulting in a switch
of HbF to adult hemoglobin.

"We have known for years that sustained expression of HbF after birth can alleviate symptoms of sickle cell disease and thalassemia," said corresponding author Mitchell J.
Weiss, PhD, chief of the Department of
Hematology at St.
Jude.
"Very high HbF levels could cure these diseases despite the defective globulin gene
.
As a result, many laboratories are focused on understanding the perinatal transition from γ-globulin gene expression to β-globulin gene expression and finding new ways
to reverse this shift with drugs or gene therapies.
”

Restore the production of HbF in adults

The St.
Jude team found that hypoxia-inducible factor 1 (HIF1) directly promotes the transcription of the γ-globulin gene to enhance HbF production
.
HIF1 is an important component of
a cell's ability to sense and adapt to hypoxic conditions.
Under hypoxic conditions, HIF1 aggregates and activates hundreds of genes in many tissues, including HbF
in red blood cells.

First author Ruopeng Feng, Ph.
D.
, a scientist in Weiss's lab, demonstrated that a drug that activates a partial cell hypoxic response can inhibit the sickling
of red blood cells from adults with sickle cell disease.
The drug is a proline hydroxylase inhibitor, which causes HIF1 to accumulate, bind to DNA regulatory regions near γ-globulin genes, activate their transcription to produce HbF, and inhibit cellular sickle cells
.
Proline hydroxylase inhibitors are currently in advanced clinical development for
the treatment of anemia associated with chronic kidney disease.
These drugs stimulate the production of erythropoietin by stabilizing the HIF protein, a hormone
that promotes the production of red blood cells.

"Our findings suggest that proline hydroxylase inhibitors may be useful for the treatment of sickle cell disease or beta-thalassemia, where initiating HbF production has therapeutic benefits
," Weiss said.
About 20% of adults with sickle cell disease develop kidney failure and associated anemia
.
Proline hydroxylase inhibitors may have a dual effect on these people by stimulating the production
of erythropoietin and HbF.
”

Associate hypoxia reactions with HbF

In 2019, the Nobel Prize in Physiology or Medicine was awarded for the discovery
of the HIF pathway.
Currently, research led by Weiss's team establishes a direct link
between this hypoxic adaptation and HbF expression.
This link explains the long-standing clinical observation that HbF is induced during accelerated red blood cell production after exposure to hypoxia or some form of anemia called "stress erythropoiesis
.
"

Weiss said: "The identification of globulins as HIF target genes supports the concept of
HbF evolving as a protective mechanism against hypoxia.
More than 50 years of research on hemoglobin have established many universal principles
in biology and medicine.
It is exciting and gratifying that studies of hemoglobin and globulin gene expression continue to yield new clinically relevant findings
.
”

Activation of γ-globin expression by hypoxia-inducible factor 1α