An Epigenetic First: Researchers Pinpoint Protein’s Role in Key Biological Process

UNC researchers help piece together how the key players in DNA methylation work together during gene regulation, a key finding needed to develop better therapies.

Epigenetic

Scientists may be closer to answering a long-standing question in biology – how do the components of our cellsmolecular machinery work together to transmit vital gene regulatory information from one cell generation to the next?

New findings published in eLife draw connections between some of these pieces, revealing an extensive web of molecular interactions that may ultimately inform the development of new epigenetic drugs to treat cancers and other diseases. Specifically, the study reveals a mechanism that helps explain how dividing cells pass on patterns of epigenetic information called methyl tags to their daughter cells. This is a crucial part of regulating how genetic information is expresed across cell generations.

Epigenetic tags help tell genes when to switch “on” and “off,” ultimately determining cell type and function. DNA methylation, or the addition of methyl tags to DNA, is one of the most well-studied epigenetic signals; errors in this process are commonly found in cancer.

“Many of the key players orchestrating DNA methylation had previously been characterized, but what we didn’t fully realize before this study is that they all work together in an elegant way,” said Scott Rothbart, PhD, assistant professor at Van Andel Research Institute (VARI) and the study’s senior author. “These new insights into the complexities of epigenetic regulation are contributing to our basic understanding of this process in human health and disease and gives us new vision for how to go about targeting errors in DNA methylation with innovative drug therapies.”

The findings center on a protein called UHRF1, a guardian of the cell’s epigenetic information that can recognize patterns of epigenetic tags and promote the addition of new ones. These “reading” and “writing” activities of UHRF1 are well understood on their own but until now, scientists didn’t know exactly how or even if these UHRF1 activities worked together. Rothbart’s team, along with collaborators from the University of North Carolina at Chapel Hill, the University of Washington, and the University of Toronto, tackled this problem by asking two questions—how does UHRF1 get to where it needs to be? And once it’s there, what does it do?

Here’s what they found: during cell division, UHRF1 recognizes newly copied DNA at sites that are missing methyl tags. At the same time, it also recognizes a protein associated with DNA called histone H3 and attaches another small protein called ubiquitin on that histone. This ubiquitin protein acts as a molecular flag, signaling to another protein called a DNA methylation enzyme that a methyl tag is needed there. The group discovered that ubiquitin attachment on the histone is promoted by the pre-existing pattern of epigenetic signals recognized by UHRF1. This is the first time an epigenetic signal has been shown to affect ubiquitylation and connects the patterns of epigenetic information in a new way.

“While the functions of the individual parts of UHRF1 were already known, we didn’t appreciate the interdependence of these functions in adding ubiquitin to histones,” said Joe Harrison, PhD, first author of the paper and a postdoctoral fellow in the lab of Brian Kuhlman, PhD, at the UNC School of Medicine. “This exquisite regulation of a ubiquitin ligase has not been previously described and is very exciting for the field of ubiqutin biology.”

DNA methylation has become a target for drug development; in fact, several of these therapies are already in clinical use for certain cancers. With this new knowledge, the next step, Rothbart says, is to develop robust screening methods to find compounds that correct errors in this process.

Rothbart’s work was funded in part by Van Andel Research Institute and the National Institutes of Health. For a full funding statement, please see the publication.

Along with Harrison and Kuhlman, Brian Strahl, PhD, was another UNC author on the eLife paper. Kuhlman and Strahl are members of the UNC Lineberger Comprehensive Cancer Center.