Researchers use CRISPR gene editing tool to analyze globin gene switching

CRISPR gene editing—a form of “molecular scissors”—was used by UNSW researchers to investigate how deletions in one section of the genome might impact the expression of surrounding genes. The research, led by UNSW Associate Professor Kate Quinlan and Professor Merlin Crossley, will enable researchers to examine novel treatment options for sickle cell disease, one of the world’s most severe genetic blood diseases.

Researchers use CRISPR gene editing tool to analyze globin gene switching
A/Prof. Kate Quinlan and Prof. Merlin Crossley. Image Credit: Richard Freeman / University of New South Wales, Sydney.

The findings of the researchers were published in the science journal Blood. A/Prof. Quinlan and Prof. Crossley were recently awarded a $412,919 ARC linkage grant to fund cooperation between UNSW Sydney and CSL that will build on the research that is detailed in this study.

Sickle cell disease and beta thalassemia, a closely related disease, are inherited genetic conditions that affect red blood cells. They are fairly common worldwide—over 318,000 infants with these conditions are born every year, and hemoglobin disorders cause three percent of deaths in children aged under five years worldwide.”

Kate Quinlan, Study Co-Lead Author and Associate Professor, University of New South Wales

The diseases are caused by genetic mutations, especially a deficiency in the adult globin gene. The mutated genes have an impact on the development of hemoglobin, a protein found in red blood cells that transports oxygen throughout the body.

Interestingly, when children are born, they don’t show disease symptoms at first, even if they have the mutations, because at that stage, they’re still expressing fetal globin and not yet adult globin. That’s because we have different hemoglobin genes that we express at different stages of development. As the fetal globin gets turned off, and adult globin gets turned on—which happens within about the first year of life—the symptoms start to manifest.”

Kate Quinlan, Study Co-Lead Author and Associate Professor, University of New South Wales

When this happens, red blood cells take on strange, sickled forms and obstruct tiny blood vessels, resulting in discomfort, organ damage, and death. The condition is particularly prevalent in tropical nations and among those who have lived in malaria-endemic areas.

A/Prof. Quinlan notes, “The goal of our research is finding out how we can reverse the fetal to adult globin switch, so that patients continue to express fetal globin throughout life, rather than the mutant adult globin genes that cause blood cells to become stiff and block vessels.”

Surprisingly, this already occurs in some persons with sickle cell disease: a small minority of patients with sickle cell disease retain the fetal globin gene “on” throughout their lives, preventing sickle cell symptoms.

In these patients, the persistent expression of fetal globin effectively compensates for the defective adult globin—but up until this piece of research, we didn’t really understand the process that led to this incredible advantage,” states A/Prof. Quinlan.

“Deleting” genes with CRISPR

UNSW PhD student Sarah Topfer collated data on the uncommon families that produce fetal globin throughout life to figure out what is going on in these lucky people’s genomes.

Sarah Topfer, PhD student says, “As a first step, Sarah compared deletions in lots of different patients’ genomes—essentially, she looked to see if any shared element was missing in all of them. What do these patients have in common? She found one very small region was deleted in all these patients’ genomes.”

Sarah then employed CRISPR gene editing in cell lines in the lab to duplicate some of these large patient deletions—as well as the little deleted part they all shared in common.

A/Prof. Quinlan explains, “CRISPR allows us to ‘cut’ bits of DNA out of cells grown in the lab, to modify genes and see what happens as a result—it’s essentially a tool to figure out what genes do inside living cells.

We found that deleting just that one little bit was sufficient to make fetal globin go up and adult globin down—which suggests that we have found the key mechanism that can explain why fetal globin levels remains high in these asymptomatic patients. Effectively, by deleting the adult globin ‘on switch’, we made the fetal globin ‘on switch’ active,” notes A/Prof. Quinlan.

The results, according to Prof. Quinlan, were surprising.

A/Prof. Quinlan says, “It was surprising to see the findings—many people have studied these mutations for many years, so the idea that there’d be one unifying hypothesis that could explain them rather than them all working through different mechanisms will be surprising for the field.”

While we went in with the hypothesis that there might be one mechanism, we didn’t expect it to come out so cleanly—we thought that perhaps it would be more complicated than what we'd initially thought,” adds A/Prof. Quinlan.

The CRISPR revolution and potential therapies

Prof. Crossley, who is also UNSW’s Deputy Vice-Chancellor, Academic & Student Life, adds that testing this concept before the introduction of CRISPR gene editing was difficult.

Our group has specialized in using this new technology to understand globin gene switching. Australia now has a significant number of people with either sickle cell disease or thalassemia. The work, supported by the National Health and Medical Research Council, is an important example of how the CRISPR gene editing revolution is accelerating scientific understanding and will deliver new therapies to the clinic."

Prof. Merlin Crossley, Deputy Vice-Chancellor, Academic & Student Life, University of New South Wales

According to the researchers, the data presented now advances the fundamental knowledge of the process behind sickle cell disease.

What this really helps us to do is understand this process of turning off fetal globin and turning on adult globin and how we could reverse that, so that we can use this understanding of the mechanism to help us look for new therapeutic approaches—it’s a key piece of the puzzle,” A/Prof. Quinlan concludes.

Prof. Crossley’s team’s prior findings in the field are already guiding clinical studies, thanks to advantageous mutations uncovered in the past that might lead to therapies for certain diseases.

Prof. Crossley earned the Prize for Excellence in Medical Biological Sciences (cell and molecular, medical, veterinary, and genetics) at the 2020 NSW Premier’s Prizes for Science and Engineering for his work in the field.

Journal reference:

Topfer, S. K., et al. (2022) Disrupting the adult globin promoter alleviates promoter competition and reactivates fetal globin gene expression. Blood.


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