After a valiant decade-long quest, scientists at the Johns Hopkins University School of Medicine say they have discovered a new role for a pair of enzymes that regulate genome function and that, when missing or mutated, link brain tumors, blood cancers and Kleefstra’s synthesis Syndrome and other diseases – a rare genetic neurocognitive disorder.
The new findings were published on November 21 in Epigenetics and Chromatinwhich could eventually help scientists understand diseases caused by the disruption of these enzymes and develop new treatments for them.
“A better understanding of how enzymes affect the activity of our genome can provide valuable insights into biology and could help researchers design new treatments for disease,” said Sean Taverna, Ph.D., Johns Associate Professor of Pharmacology and Molecular Sciences. Hopkins University School of Medicine.
The research began more than a decade ago, when Taverna was looking for factors that affect the DNA activity of Tetrahymena thermophila, a single-celled freshwater organism. In the original study, the team discovered a previously unknown signal that a single-celled organism uses to “mark” genes it has turned off.
The marks are located on histones, which act as spools and tightly wind the DNA, normally shutting down genes and protecting the DNA from damage. If the Tetrahymena couldn’t add the mark — a process called methylation, which adds a chemical mark to part of a histone called H3K23 — the DNA was damaged and the cells grew poorly.
In a follow-up study published in 2016, Taverna found that the H3K23 position is conserved between Tetrahymena and mammals, including humans. However, the enzymes that control how chemical tags are placed on H3K23 vary among species.
Without these enzymatic H3K23 methylation “writers,” researchers have found it difficult to study the role of H3K23 in human biology and disease.
So, Taverna, recent Ph.D. David Vinson, MD, professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, and Srinivasan Yegnasubramanian led a new study to find the mammalian enzyme that adds a chemical tag to H3K23.
After screening many enzymes that write methylations, Vinson found only a pair of enzymes, EHMT1/GLP and EHMT2/G9a, that place chemical tags at H3K23 histone positions.
When the researchers used drug inhibitors and genetic mutations targeting the enzyme pair in lab-grown human brain cells (neurons), the enzyme’s ability to place methylation tags on H3K23 histone sites was significantly reduced.
“With this initial precedent established in human neuronal cells, the door is now open to study the role of these enzymes and H3K23 modifications in the context of many health and disease conditions, including human cancer,” Yegnasubramanian said.
Now that the researchers know that EHMT1/GLP and EHMT2/G9a place chemical tags at H3K23 histone positions, they aim to understand the precise mechanism of how they do so and develop drugs that target this activity.
“We want to better understand why disease occurs when these enzymes don’t work properly, and their connection to H3K23,” Taverna said.
In addition to Taverna, Yegnasubramanian and Vinson, other researchers who contributed to the study were Kimberly Stephens of the University of Arkansas for Medical Sciences; Robert N. O’Meally, Shri Bhat and Robert Cole of Johns Hopkins University; and Walter Blair Dancy of the Reed Army Institute.
Funding for this study was provided by the National Institutes of Health (R01GM118760, R01CA221306, and F31GM130114), the National Science Foundation, the Irving A. Hansen Memorial Foundation, and the Commonwealth Foundation.
