Researchers Identify Key Regulator of Blood Stem Cell Development
A protein that masterminds the way DNA is wrapped within chromosomes has a major role in the healthy functioning of blood stem cells, which produce all blood cells in the body, according to a new study from researchers at Weill Cornell Medicine.
The protein, known as histone H3.3. Histones enable DNA to be tightly compacted, and serve as platforms for small chemical modification that can loosen or tighten the wrapped DNA to control local gene activity.
The study found that H3.3 is crucial for both processes; deleting the protein from HSCs led to reduced HSC survival, an imbalance in the types of blood cell produced by the HSCs and other abnormalities.
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.
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.
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.
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