International Business Department           Liu Bojia           October 17, 2024

  Scientists studying cancer discovered early on that up to 60% of adult leukaemia cases, as well as some other types of cancer, are linked to a gene called TET2. In addition to cancer, TET2 mutations have been found to increase the risk of heart disease, stroke, diabetes, and other inflammatory diseases. However, why mutations in the TET2 gene or its related genes cause so many problems is an unsolved mystery.

  Recently, a research team led by Professor He Chuan of the University of Chicago and Professor Xu Mingjiang of the University of Texas Health Science Center at San Antonio published a paper in the journal Nature, unravelling the mystery of the carcinogenicity of TET2 mutations, and their discovery also provides targets for the treatment of a variety of diseases.

  Professor He Chuan is a pioneer in the field of RNA epigenetics, and over the past decade or so, he has pioneered the discovery that cellular gene expression is not only regulated by DNA modifications and protein modifications, but also by reversible modifications on RNA, such as RNA methylation. To date, more than 170 modifications have been identified on RNA, such as m5C, m6C, m7G, etc. These RNA modifications play important roles in a variety of diseases such as cancer.

  In this study, the team led by Professor He Chuan found that when TET2 is defective, it actually affects the methylation modification of RNA as well, and does not act on DNA methylation as the classical functions of the TET family that have been discovered in the past.

  Through a series of gene editing and analysis techniques, the team found that the TET methylcytosine dioxygenase encoded by TET2 regulates the frequency with which chromatin-associated retrotransposon RNAs (or caRNAs for short) undergo m5C methylation, which, in turn, affects the open state of chromatin. Specifically, when m5C methylation of retrotransposon RNAs is preserved, they can be recognised by the methyl CpG-binding structural domain protein MBD6, which recruits deubiquitination complexes and increases chromatin opening. This is important early in life, when stem cells need to actively differentiate into various cell types, and chromatin in a more open state favours gene expression.

  And while in adulthood, TET2 maintains chromatin tightness by oxidising the m5C of caRNA, TET2 deletion is equivalent to loosening the reins that should be tightened, allowing chromatin to open up even further, increasing transcription within the stem cell and reopening the growth pathway - uncontrolled growth that could ultimately lead to cancer.

  The experimental results showed that TET2 mutant leukaemia is the result of abnormal gene activation within haematopoietic stem cells. When researchers knocked down MBD6 in TET2-deficient leukaemia cell lines to re-enforce control over chromatin accessibility status, they found that they could inhibit the growth of cancer cells. In a mouse model, knocking down MDB6 largely reversed the haematopoietic defects caused by Tet2 deletion.

  The authors note that this exciting result shows the promise of MBD6 downstream of TET2 as a new target for the development of anticancer drugs against TET2 mutations. Not only that, some patients have blood cells with TET2 mutations that have not yet caused cancer, but the mutant cells with inflammatory properties affect vital organs such as the heart and liver as they circulate in the bloodstream, so based on the findings of this study, it may also be possible to prevent related diseases by eliminating these mutant cells.