Harvard Medical School (HMS) scientists have identified a key molecule that helps push very early embryonic cells down the road to becoming a specific organ or tissue. Though the molecule, CBP-1, occurs in worms, it is very similar to one found in humans. The discovery, which appears in the January EMBO Reports, has implications for therapeutic cloning and cancer research.
“To do cloning in higher organisms you have to understand how tissues form,” said Yang Shi, HMS associate professor of pathology. “You have to know how pluripotent cells adopt specific cell fates. Our focus here is to really understand these fundamental questions.”
Most human cloning efforts, including the recent venture by Worcester-based Advanced Cell Technology (ACT), aim to produce a store of personalized stem cells that can be used to repair or even replace damaged or diseased organs and tissues. Though fraught with challenges, such attempts could be aided by the new findings, especially in the very early stages of cell development. For example, ACT produced only six-cell human embryos. Shi, Martin Victor, research fellow in pathology, and their colleagues found that their newly discovered molecule acts at the four-cell stage in worms. The findings could help researchers understand how to push very early embryos further down the development pathway.
Moreover, the researchers have discovered how the molecule functions at the level of DNA, a discovery that could provide insight into how cells adopt their various fates. Normally, DNA, including that of humans, is tightly wound around spools of proteins, called histones, leaving little room for the proteins that come in to turn on genes. The researchers found that CBP-1 works by loosening the DNA thread in the region of a fate-determining gene, thereby allowing the gene to be turned on.
This process, which entails the addition of acetyl groups, is a subject of great scientific interest. “A lot of scientists are studying acetylation,” said Shi. But it is only half the story. In a paper appearing in the December EMBO, Shi, Dominica Calvo, research fellow in pathology, and colleagues reported that while worm cells destined to become the intestine require the turning on of the fate-determining gene, those destined to become muscle cells need the gene to be kept off. This in turn requires that the DNA-loosening acetyl groups added by CBP-1, which is present in such cells, be removed by other proteins. Shi and his colleagues identified a deacetylation complex consisting of at least three proteins.
“It’s the balance between these two activities – acetylation and deacetylation – that will determine whether a gene is going to be on or off, and whether the cell will develop one way or another,” said Shi.
In fact, an imbalance in these two activities could give rise to cancer. Several years ago, researchers showed that the human version of the CBP-1 gene, when mutated, causes tumor formation. The human homolog, p300, appears to be mutated in certain human cancers, suggesting Shi’s findings could shed some light on the disease. For example, such cancers may form because the acetylation process, which enables developmental genes to be turned on, is disrupted. With no developmental path to follow, the cells keep cycling, eventually turning into a cancerous mass.
One way to rescue such cells would be to restore acetylation. Another possibility would be to prevent deacetylation from happening. “You might do this by modulating their activity by small molecules,” Shi said. A compound intended to inhibit deacetylation proteins is in clinical trials for treating some forms of leukemia.