Dual epigenetic marks found to regulate cell identity

Shedding light on what determines how cells become what they are meant to be-nerves, bone, muscles, etc.-can also help researchers understand how diseases develop when these biological programs break down.

Now, researchers at Case Western Reserve University have discovered a key synergistic role for two epigenetic markers-molecules that help tell genes to turn on and off-involved in programming cell fate. Importantly, turning off these two markers causes genes to over-activate, disrupting normal cell development.

The research is published in the journal Science Advances. The findings have importance for understanding neurodevelopmental diseases and may indicate a new target for treating some types of leukemia with drugs already in clinical trials for treating other cancers.

No one understood how these markers worked together, and now we have a mechanism. Not only that, but we also think there could be a therapeutic impact."

Kaixiang Cao, principal investigator, assistant professor of biochemistry and genetics and genome sciences at the Case Western Reserve School of Medicine and member of the Case Comprehensive Cancer Center

Epigenetic mechanisms play a central role in regulating cell fate during normal development and in disease. Deciphering these mechanisms shed light on developing novel therapies for treating human developmental syndromes and cancer.

In model organism stem cells, the research team used cutting-edge genetic engineering to remove the enzymes responsible for adding epigenetic markers called H3K79 methylation and H3K36 trimethylation-one at a time and together. They discovered that removing either mark alone caused only minor changes, but losing both at once sent gene activity into overdrive and blocked the cells' ability to become neurons.

"To our surprise, when we removed the markers, we found that the genes were over-activated," said Cheng Zeng, a CWRU graduate student who contributed significantly to this study and received his PhD in biochemistry this month from the medical school. "When people have looked at these markers individually, it seemed as though they were involved in turning genes on, so removing them was thought to turn the genes off. It was actually the opposite."

While these markers are implicated in rare neurodevelopmental diseases, they are more prevalent in cancer, said Cao, who cited Case Western Reserve's collaborative research culture and support for team's promising findings.

In leukemia, a cancer of the blood, defects in methylation may cause blood stem cells to fail to differentiate properly into mature red and white blood cells. The study identified a potential new treatment strategy: blocking a protein partnership (YAP-TEAD) that becomes overactive when both methylation marks are missing.

In a specific cohort of patients carrying a misregulation in both epigenetic marks, Cao said treatment targeting the YAP-TEAD pathway might prove successful.

Drugs targeting the YAP-TEAD pathway are already in clinical trials for treating other types of cancers, like mesothelioma (a type of cancer that affects the lining of the lungs or abdomen). These drugs were not previously considered for treating leukemia having abnormal methylation.

The hypothesis would have to first be tested in clinical models of the disease before moving to human trials.

Collaborators on the research include: Fulai Jin, a professor in genetics and genome sciences at the medical school and co-leader of the cancer genomics and epigenomics program at the Case Comprehensive Cancer Center; CWRU biochemistry research assistant Emmalee Cooke; and researchers at Fudan University in Shanghai. The research was supported by the U.S. National Institutes of Health.