A recent study by scientists at the University of Chicago has unveiled a crucial role of RNA in DNA packaging and storage within cells, linked to a gene known as TET2. This discovery sheds light on why many cancers and disorders involve TET2-related mutations and suggests new targets for treatment.
The research, published in Nature on October 2, was led by UChicago Professor Chuan He in collaboration with Professor Mingjiang Xu from the University of Texas Health Science Center at San Antonio. "This represents a conceptual breakthrough," said He, highlighting its potential impact on therapy for several diseases and the broader understanding of chromatin regulation.
He’s lab has previously contributed to the understanding of gene expression through RNA modifications. Their focus on TET2 revealed that it affects RNA rather than DNA, challenging previous assumptions. The study found that TET2 controls how often a modification called m5C occurs on certain types of RNA, which attracts a protein known as MBD6 that influences chromatin packaging.
"If you have a TET2 mutation, you reopen this growth pathway that could eventually lead to cancer—especially in the blood and brain," explained He. Experiments showed that removing MBD6 in leukemia cells caused them to die, suggesting new drug targets.
"What we hope we can get from this is a silver bullet to selectively get rid of just cancer cells," said He, who is working with UChicago’s Polsky Center for Entrepreneurship and Innovation to develop such treatments.
TET2 mutations also occur in older adults, increasing risks for heart disease and other conditions. Oncologist Caner Saygin noted the potential benefits of eliminating mutant cells before they cause cancer: "Right now, I cannot prescribe anything to these patients because they don’t have cancer yet."
The findings also suggest a broader mechanism for chromatin regulation involving RNA methylation. "If there’s a second [mechanism], you could have a third, fourth, fifth," said He. "We think this pathway is just the tip of the iceberg."
Citation: “RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis.” Zou, Dou, and Li et al., Nature, Oct. 2, 2024.
Funding: National Institute of Health