Just one in 2,000 bone marrow cells is a hematopoietic stem cells (HSC), but these cells are the source of the ten billion blood cells that the human body makes every day. The results of research in mice by scientists at the Centre for Genomic Regulation (CRG), Barcelona, have now shown that the epigenetic regulator Phf19 is essential for HSC differentiation, and in its absence blood tissue is imbalanced, much as it becomes with aging. The findings could have implications for cancer research, the scientists believe, and provide “novel insights into how epigenetic mechanisms determine HSC identity, control differentiation, and are key for proper hematopoiesis,” they wrote in their published paper in Science Advances.
“… the study of the processes by which stem cells regulate genetic information to produce specialized cells is essential for understanding how cells acquire pluripotence and proliferation capacity, key characteristics to form tumors,” said Pedro Vizán, PhD, co-first author of the study. The results demonstrated that “the lack of Phf19 increases the probability of suffering disorders in the composition of the blood. That is why we are studying its possible role as a precursor of tumors or whether it would be an anticancer therapeutic target.” The researchers’ findings are reported in a paper titled, “The Polycomb-associated factor PHF19 controls hematopoietic stem cell state and differentiation.”
Blood is a complex tissue made up of different specialized cells, including white blood cells, red blood cells, and platelets, which all perform various essential functions including the transport of oxygen and nutrients, maintaining body temperature, and carrying out immune system functions. All blood cells are generated from HSCs, which are precursor cells stored in the bone marrow. “Blood regenerates at a high level, providing an ideal platform for studying stem cell function,” the team explained.
Blood diseases affect a large part of the worldwide population. One in four people suffers from anemia, 17 out of 100,000 have hemophilia, and 2.5 out of 100 tumors that are detected worldwide are leukemic in nature. All of these abnormalities are the result of malfunctioning blood cells or imbalances in the composition of blood tissue.
Maintaining blood tissue balance is complex because each cell type has a different lifespan. For white blood cells, it is about 5–20 days, while the lifespan of red blood cells is about 120 days. To renew each of these cell types in the face of a threat such as a wound or bleeding, HSCs, which normally remain dormant, begin to divide and produce specialized cells to maintain the balance of blood tissue.
The process of transition from HSCs to specialized cells is regulated by epigenetic factors, which play a role in controlling which genes are expressed. The CRG-led researchers, headed by Luciano Di Croce, PhD, a group leader at CRG, were particularly interested in the Phf19 gene, which is part of a large group of epigenetic regulators known as the Polycomb group (PcG). Phf19 is a subunit of the Polycomb repressive complex 2 (PRC2). “Bone marrow cells are constantly dividing and are very sensitive to environmental factors such as radiation or chemotherapy,” explained Arantxa Gutiérrez, PhD, lab manager in the Di Croce lab and co-first author of the article. “Any changes that affect the gene expression of HSCs, including epigenetic factors, can have a major impact on blood balance due to the plasticity of these cells.”
In their published study, the CRG researchers described the role of the epigenetic regulator Phf19 in maintaining HSCs. They genetically modified mice to remove the Phf19 gene without affecting normal lifespan. Without the gene, the regions of the genome containing the genes responsible for HSC differentiation were more compacted, and specific gene expression was repressed. As a consequence, HSCs remained quiescent and did not differentiate as much into the specialized blood cells. “Here, we now show that, in stark contrast to results published for other PRC2 subunits, genetic depletion of Phf19 increases HSC identity and quiescence,” they wrote. “At the molecular level, PHF19 deletion triggers a redistribution of the histone repressive mark H3K27me3, which notably accumulates at blood lineage–specific genes … Together, our data indicate that the absence of PHF19 produces an epigenetic rewiring of HSCs, leading to an enhancement of stem identity likely instructed by aberrant repression of differentiation programs.”
The researchers found that under normal conditions the knockout mice continued to live healthily, but under certain situations, such as when undergoing transplants or as the aged, the difficulty in producing differentiated cells compromised the proper functioning of blood tissue. In the long term, animals lacking Phf19 accumulated disorders in the composition of blood, which were similar to those of the early stages of leukemia.
“The vast majority of studies that have been done so far have removed all the biochemical functions from the multiprotein complex of which Pfh19 is part, both in mice and in humans,” Di Croce explained. What wasn’t previously known was that PHF19 controls HSC activation to begin to specialize. “Until now it was known that aging conditioned the quantity and activity of the PHF19 protein and other proteins of the complex that it is part of, both in mice and in human … We have taken a subtler approach by eliminating a single gene, allowing us to discover an unexpected role in the regulation of MHC.”
The authors concluded, “… our results indicate that PHF19 is necessary to maintain a correct hematopoietic balance and that its depletion induces an aberrant state, which primes HSCs for malignant progression … Our results provide novel insights into how epigenetic mechanisms determine HSC identity, control differentiation, and are key for proper hematopoiesis.”