Dr. Tarik Möröy

As President and Scientific Director of the Institut de recherches cliniques de Montreal (IRCM), an institution affiliated with the Université de Montréal, Dr. Tarik Möröy balances the demanding roles of an administrator and fundraiser with his duties as Director of the Hematopoiesis and Cancer research unit, where he pursues his love of science.

In the laboratory, he works with transcription factors – small proteins that regulate gene expression. He focuses on a process called hematopoiesis, that is the formation all our blood and immune cells. He is particularly interested in the hematopoietic- or blood stem cells, which are located in the bone marrow. These stem cells give rise to all cells in the blood, including red blood cells, B-lymphocytes and T-lymphocytes, macrophages, and platelets. 

“Hematopoietic stem cells have an indefinite potential for self-renewal,” he says. “The way that these stem cells differentiate and decide what cells to make is controlled in part by the regulation of transcription.”

When something goes wrong with the transcription process, he explains, there is a significant risk that a blood cancer or leukemia will form.

Transcribing DNA code

Transcription factors sit on DNA, where they regulate gene expression – that is to say, whether a gene is turned on or turned off. Strands of DNA are wound around small groupings of proteins, called histones, to condense the overall length of DNA and to regulate the accessibility of the DNA strand to transcription factors.

Dr. Möröy and his team of researchers are currently working with two transcription factors, Gfi1 and Gfi1b, in blood stem cells. “Gfi1 and Gfi1b sit near where the gene is transcribed and modify the histones in such a way that they don’t allow transcription, he explains. “They package the DNA a little denser, so that the polymerase that makes RNA can’t really work.”

“Gfi1 and Gfi1b are silencers, repressors of gene expression,” he says. “They turn genes off.” Silencers crowd DNA nucleotides closer together – coiling DNA more tightly around histones. When this happens, the gene transcription machinery can no longer access the specific sections of DNA code that it needs to transcribe the code and make a protein.

Their groundbreaking work has led to a number of discoveries, contributing to the world’s knowledge of how these transcription factors work and how mutations in these genes contribute to blood diseases.

The two factors collaborate in ways that aren’t yet fully understood. They regulate each other by auto-regulatory and cross-regulatory feedback loops, which complicate the story.

“If you get rid of one factor, the other protein can still neutralize some but not all of the bad effects,” Dr. Möröy explains. “But if you get rid of both Gfi1 and Gfi1b, which is an experiment that we’ve done, then no hematopoietic stem cells are formed.”

Unraveling the mysteries of Gfi1 and Gfi1b

In 2002, Dr. Möröy and his research team were the first to knock out the Gfi1 gene in mice. They found that the altered mice had no neutrophil granulocytes. “That was a major discovery, because it revealed that Gfi1 is a regulator of granulocyte differentiation,” he says.

Granulocytes are an essential player in the body’s innate immune system. These cells, for instance, rush to open wounds to ingest invading bacteria and prevent infection.

“We didn’t expect that,” says Dr. Möröy. “We expected that loss of Gfi1 would affect the numbers or function of lymphocytes. This also happened in Gfi1 deficient mice, but the effect was mild in comparison to what the new phenotype, the new discovery, showed us.

“On the other hand, if a mouse lacks the other factor, Gfi1b, granulocytes are made but now red blood cells are not properly formed and these mice die even before birth, very likely because they are unable to transport oxygen.”

His goal is to understand how these regulators of blood cell formation contribute to what goes wrong in leukemia. “This understanding may provide hints of how to design new therapies to interfere with the disease”.

In another important discovery in 2010, Dr. Möröy’s team found that Gfi1b regulates the number of blood stem cells. If Gfi1b is not present, blood stem cells multiply uncontrollably and migrate from the bone marrow to the blood and invade other organs.

“The interesting part of this discovery is that the expansion of stem cells is a good thing in some therapies against leukemia,” explains Dr. Möröy, particularly hematopoietic stem cell transplantation – commonly known as stem cell therapy.

Before hematopoietic stem cells can be transplanted from a healthy donor to someone with leukemia, all of the recipient’s blood cells are destroyed to rid the body of leukemic cells. The newly transplanted stem cells must rebuild the recipient’s whole blood-forming system.

Manipulating Gfi1b might allow transplanted stem cells to expand rapidly in number, making this therapy more effective in patients with leukemia, he believes. “That’s not yet proven, but we have laid hands on a regulator of stem cell expansion – a regulator that controls stem cell numbers, and I think that’s very important.”

Building on success

Dr. Möröy and his team have also found that Gfi1 is involved in the formation of T-cell leukemia, which may also lead them to new discoveries that may help to design new anti-cancer therapies. In addition, the group is now expanding their research to other transcription factors that interact with Gfi1 and regulate Gfi1 activity.

They are also looking at transcription factors that affect RNA splicing. This process enables one gene to make many different proteins by reshuffling DNA coding sequences.

“In 2006, we discovered that Gfi1 could influence this process. How exactly, Gfi1 does this, we don’t know, but we had seen that this particular function influences the immune response exerted by T-lymphocytes. This was a new discovery that extended the function of Gfi1 from a transcription factor to a regulator of RNA splicing.”

Painstaking work

Gfi1 and Gfi1b work by recruiting enzymes to DNA that modify histones, groupings of proteins around which DNA is wrapped. Many of these histone-modifying enzymes can be recruited to DNA by other transcription factors, which in turn interact with Gfi1 or Gfi1b – all of these modifications end in large protein complexes that sit on DNA to fine-tune gene activity. Even with computer modeling, sorting out the multilayered effects of transcription factors is painstaking – but interesting – work.

“Why is it fun? Because sometimes you can make a discovery that you haven’t planned. That’s the way science often works,” Dr. Möröy says. “You do experiments that you think will give you a clear answer to what you’re asking but, often, you get a different answer and make an even more interesting discovery.

“When it happens, it’s very satisfying – as if you’ve found the puzzle piece that you were always looking for, and it fits exactly where you want it to fit.”

Dr. Möröy holds the Canada Research Chair in Hematopoiesis and Immune Cell Differentiation and his work is funded by the Canadian Institutes for Health Research, The Cancer Research Society and the Roche Foundation for Anemia Research.

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