Researchers at the La Jolla Institute for Immunology have uncovered how the deletion of TET (ten-eleven translocation) protein genes can lead to cancer growth. The study, published in Nature Communications, is the first to demonstrate the immediate consequences of deleting all 3 genes from the TET family in mouse embryonic stem cells.
Going TET-à-TET with proteins
Anjana Rao, senior author of the recent study, was the first to discover the TET family of proteins and has since shown how vital they are to cell growth and development. These proteins alter DNA methylation patterns and can protect against cancer-causing mutations, inflammation, and cardiovascular disease.
Her work has also proved crucial in understanding how they function in immune cells. “Dr. Rao showed that every time you have a deletion of a TET gene in these cells, you see the development of a different aggressive type of cancer,” said co-author Hugo Sepulveda.
In the current study, the team at La Jolla discovered that cells with missing or impaired TET proteins tended to have aneuploidies, uncovering another link with cancer (see Figure 1). Aneuploidies occur when genetic material is deleted or added on a much bigger scale than usual – cells with aneuploidies exhibit multiple gene losses across an entire chromosome. They are a common feature of cancer cells.
In a bid to understand whether TET loss of function was triggering aneuploidies or vice versa, the researchers turned to mouse embryonic stem cells as a model.
A new route to aneuploidy
The mouse models allowed them to see how deleting TET proteins would alter certain biological processes. They found that TET proteins are critical for both cell and DNA replication. Without them, the genes go haywire and are either lost, lead to mutations, or trigger the development of aneuploidies.
In fact, they found that cells with TET deletion developed aneuploidies at three times the rate of normal cells. The altered cells lost genes very quickly and randomly, and effects could be observed even in early embryos. “That proved that TET deletion had a direct effect on aneuploidies,” said Sepulveda. “That was very exciting and had not been shown before.”
Further RNA sequencing analysis showed that TET proteins cause a downregulation of genes associated with cell and DNA replication. Discovering this link between TET loss of function and aneuploidies is a key breakthrough for cell biology and cancer research, though the story doesn’t end there. “We can now understand the mechanisms behind aneuploidy development, although we can’t say these changes always happen through the same genes in other cell types,” said Sepulveda.
Moving on from embryonic stem cells
The mechanism behind TET proteins and their link with aneuploidy seems to lie in a gene called Khdc3. The protein encoded by this gene belongs to a complex previously studied for its activity in helping oocytes divide. It is known to maintain genome stability in oocytes before and after fertilization and in the early stages of embryonic development. The researchers found that TET loss of function results in decreased Khdc3 expression and in embryonic stem cells, this loss affects genome instability. When the protein function (KHDC3) was restored in these cells, genome stability returned, and aneuploidy was reversed.
More research is needed to determine whether the same process drives aneuploidy development in other cells, but the findings point to new avenues for future research. Sepulveda is careful to note that the Khdc3 complex is only known to be active in early embryonic cells.
“Genome instability in cancer cells could be happening through genes other than Khdc3, but through a similar regulatory mechanism that also involves changes on DNA methylation patterns,” said Sepulveda. “Whether TET-associated cancers develop aneuploidies by dysregulating different genes than Khdc3 is still an open question.”
Going forward, Sepulveda hopes to uncover exactly how the Khdc3 complex promotes genome stability downstream of TET proteins in embryonic stem cells.