Researchers uncover genetic 'bridge' to leukemia progression
For cells to thrive, a complex network of three-dimensional structures assembles to read, copy and produce the genetic materials (DNA) needed for cellular function. Understanding how these structures form, and what happens when things go wrong, is an everyday endeavor for researchers at Penn State College of Medicine and Penn State Cancer Institute.
In the lab of Four Diamonds Epigenetics Program researcher Suming Huang, professor of pediatrics, a team of scientists is studying how certain hard‐to‐treat subtypes of acute myeloid leukemia (AML) develop as a result of alterations in cellular genome structures, called topologically associated domains (TADs). Huang is investigating how long noncoding ribonucleic acid (lncRNA) affects the function of the human genome building block, called CCCTC-binding factor (CTCF), in the formation of these topological structures. According to his latest study, which was published in Molecular Cell, a lncRNA called HOTTIP plays a key role in the formation of R-loops with DNA strands, which maintain the structural integrity needed for downstream biological processes that allow leukemia to develop and progress.
"Imagine a suspension bridge," said Huang, a Cancer Institute researcher. "The bridge itself is the TAD that allows access to the production line for a molecule called beta-catenin, which prior research has shown allows leukemia cells to develop. The bridge is assembled and supported by the towers (CTCF) and cables (HOTTIP) and the cables are anchored in place by the R-loops. Our lab demonstrated that R-loop formation is facilitated by HOTTIP."
To arrive at their conclusion, the researchers conducted experiments with mice implanted with AML cells. Some mice received genetically altered AML cells unable to form R-loops in the TAD encompassing beta-catenin region, whereas another set had AML cells that were able to form R-loops in this region. On average, the mice with the cells that couldn't form R-loops had a longer period of survival, which demonstrated to the team that R-loops do play a key role in leukemia development.
"Without the 'anchors,'" the genetic 'bridge' cannot form," Huang said. "Understanding how genome structure contributes to leukemia development might someday allow us to identify therapeutic targets and develop next‐generation therapies."
More information: Huacheng Luo et al, HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia, Molecular Cell (2022). DOI: 10.1016/j.molcel.2022.01.014. doi.org/10.1016/j.molcel.2022.01.014
Journal information: Molecular Cell
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