Unraveling the mechanisms that direct cells to become various tissues like nerves, bones, or muscles also aids in understanding disease progression when these cellular programs malfunction. Researchers at Case Western Reserve University have identified a crucial synergistic function of two epigenetic markers—in molecules that regulate gene activity—in guiding cell differentiation. Significantly, inhibiting both markers results in gene overactivation and disrupts normal cell development.
The study is published in the journal Science Advances. These findings may shed light on neurodevelopmental disorders and suggest a novel therapeutic target for treating certain leukemias using drugs currently in cancer treatment trials.
Science Advances"We've identified how these markers interact, which was previously unknown," said principal investigator Kaixiang Cao, an assistant professor of biochemistry, genetics, and genome sciences at Case Western Reserve School of Medicine and member of the Case Comprehensive Cancer Center. "There may also be potential therapeutic applications."
Epigenetic mechanisms are vital in regulating cell fate during normal development and disease processes. Understanding these mechanisms could lead to novel treatments for developmental syndromes and cancers.
Using advanced genetic engineering techniques on model organism stem cells, the research team removed enzymes responsible for epigenetic markers known as H3K79 methylation and H3K36 trimethylation—individually and in combination. They found that removing either marker alone caused minimal changes, but removing both simultaneously led to excessive gene activation, preventing cells from developing into neurons.
"Contrary to expectation, we discovered that when these markers were removed, genes became overactivated," said Cheng Zeng, a Ph.D. student who contributed significantly to this study. "Individual examination of these markers suggested they activate genes, so their removal should deactivate them. However, it was the opposite."
While these markers are linked to rare neurodevelopmental diseases, they are more common in cancer, as noted by Cao, crediting Case Western Reserve's collaborative research environment for supporting their groundbreaking work.
The study proposes a potential therapeutic approach in leukemia: inhibiting a protein partnership (YAP-TEAD) that becomes overactive when both methylation marks are absent.
This treatment could benefit patients with abnormal regulation of both epigenetic markers. Cao mentioned that drugs targeting the YAP-TEAD pathway are already in clinical trials for other cancers, such as mesothelioma.
The study also involved collaborations from Fulai Jin, a professor at Case Western Reserve and Fudan University in Shanghai.