A Key Regulator of Blood Stem Cell Development has been Identified by Researchers

According to a new study from Weill Cornell Medicine researchers, a protein that controls how DNA is wrapped within chromosomes plays a key role in the correct functioning of blood stem cells, which produce all of the body’s blood cells.

In plants, mammals, and most other species, the protein is known as histone H3.3 organizes the spool-like structures around which DNA is coiled.

Histones allow DNA to be compacted securely and serve as platforms for epigenetic changes, which relax or tighten the bundled DNA to govern local gene activity.

H3.3’s role in blood stem cells, commonly known as hematopoietic stem cells (HSCs), was investigated in the study, which was published in Nature Cell Biology on 27th December 2021. HSCs are a significant focus of attempts to develop stem-cell-based therapeutics.

Most HSCs remain in a stem-like, uncommitted condition where they can survive indefinitely while slowly self-renewing, while some HSCs develop or “differentiate” to produce all of the different lineage-specific blood cell types.

H3.3 is required for both processes, according to the research, and removing it from HSCs resulted in decreased HSC survival, an imbalance in the types of blood cells produced by the HSCs, and other abnormalities.

Most importantly, we found evidence that H3.3 has its effects on HSCs in part by anchoring several key epigenetic marks at developmental genes and endogenous retroviruses (ERVs); which are remnants of viruses that once inscribed themselves into our distant evolutionary ancestors’ DNA.

Dr. Ying Liu

“How hematopoietic stem cells coordinate their self-renewal and differentiation into various blood cell types in a balanced way has been a mystery to a great extent, but this study helps us understand those processes much better at the molecular level and gives us many new clues to pursue in further investigations,” said study co-senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor in Genetic Medicine at Weill Cornell Medicine.

Dr. Ying Liu and Dr. Peipei Guo, both senior instructors in the Rafii Laboratory, were co-first and co-senior authors, as were co-senior author Dr. Duancheng Wen, assistant professor of reproductive medicine research in obstetrics and gynecology, and co-author Dr. Steven Josefowicz, assistant professor of pathology and laboratory medicine and a member of the Sandra and Edward Meyer Cancer Center, all of Weill Cornell Medicine.

Because of their relevance in health and disease, as well as their promise in regenerative therapy, HSCs are among the most studied stem cells.

From red blood cells and platelets to T cells, B cells, and pathogen-eating macrophages, a single HSC can give rise to all sorts of blood cells. A deeper understanding of how HSCs function could lead to a variety of applications, such as lab-grown blood for transfusions and improved HSC transplants for cancer patients.

Furthermore, understanding how HSCs become leukemias after receiving aberrant mutations could lead to the development of new therapeutics for these often-refractory malignancies.

In recent years, biologists have become increasingly interested in H3.3, as evidence of its involvement in HSCs and other stem cells, as well as its function in many malignancies when mutated, has accumulated. However, it is unclear what histone H3.3 performs in HSCs and other cell types where it is found.

“Added to the complexity of this project, is that two different genes (H3.3A and H3.3B) code for the same H3.3 protein. Therefore, we had to painstakingly delete both genes in mice by genetic engineering, a herculean task that required a great deal of genetic manipulation of stem cells,” Dr. Wen said.

“Our powerful mouse model allows inducible and complete deletion of the H3.3 protein in all organs, or specific types of organs, at selected developmental stage of a mouse,” said Dr. Liu, who is also a research associate in Dr. Rafii’s lab.

“Employing this approach, we showed that H3.3’s absence in adulthood primarily causes a depletion of the long-term, self-renewing HSCs on which future blood-cell production depends. At the same time, affected HSCs differentiated into mature blood cell types with an abnormal skew or bias towards certain types of white blood cell, including granulocytes and macrophages.”

“Most importantly, we found evidence that H3.3 has its effects on HSCs in part by anchoring several key epigenetic marks at developmental genes and endogenous retroviruses (ERVs),” she added, “which are remnants of viruses that once inscribed themselves into our distant evolutionary ancestors’ DNA.”

“One intriguing observation was that H3.3’s deletion caused the loss of epigenetic marks that normally suppress ERVs, which led in turn to the activation of an inflammatory response in affected cells, and then drove the cells’ skewed production of blood cell types a skew that is similar to what is seen in some leukemias,” said Dr. Guo, who is also a research associate in Dr. Rafii’s laboratory.

“H3.3 appears to be acting as a master regulator of self-renewal and differentiation in HSCs which is wild, and hints at a very broad potential as a therapeutic target someday,” said co-author Andrew Daman, a Weill Cornell Graduate School of Medical Sciences doctoral candidate in the Josefowicz lab.

“Our take-home message is that normal blood cell development requires the proper epigenetic regulation provided by H3.3,” Dr. Liu said.

The researchers are now planning more research in HSCs and other cell types to learn more about how H3.3 works and what happens when it isn’t there. More crucially, finding methods to track the H3.3 command of the epigenetic landscape could help them raise blood production more effectively.

“Finally, our team is investigating how H3.3 controls the function of the nurturing niche cells, such as blood vessels that orchestrate stem cell self-renewal and possibly block the emergence of malignancies such as leukemias,” said Dr. Rafii, who is also a member of the Meyer Cancer Center.

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