By Rachel Scanza, Ph.D.

CHARGE syndrome is a rare yet devastating congenital condition affecting tissues and organs such as the heart, nerves, genitals, eyes, and ears. Over 90% of cases arise from mutations in a single gene, Chd7, which is critical for the proper development of neural crest cells, versatile cells of the embryo that form diverse structures in the body. Until now, scientists didn’t fully understand how Chd7 becomes activated within the neural crest during development.

New research from the Stowers Institute for Medical Research has shown that Chd7 relies on specific regions in DNA, called enhancers, to “turn on” at the right time and in the right cells, including neural crest cells. Like genetic switches, these enhancers interact with special proteins to jumpstart Chd7 activity in specific tissues. The findings suggest that mutations in these neural crest-specific enhancers may contribute to cases of CHARGE syndrome without changes in the Chd7 gene itself, offering a potential path for further research and potential treatments.

“We wanted to know how and why Chd7 has elevated activity specifically in neural crest cells,” said Ruth Williams, Ph.D., a former researcher in the lab of Stowers Investigator Tatjana Sauka-Spengler, Ph.D., and now an MRC Career Development Fellow at the University of Manchester.

Williams, who led the recent study published on October 30, 2024, in PLOS Biology added, “For congenital conditions like CHARGE syndrome, which is caused by problems in neural crest development, finding the enhancers that boost gene activity could lead to new gene therapy options—especially when the exact cause of these conditions isn’t known.”

During development, genetic circuits determine how cells gain their functions. Starting from just a single cell, these circuits called gene regulatory networks control how and when various genes are turned on or off to provide proper instructions for every cell in the body. Special proteins govern these networks. This includes neural crest master regulators that specifically interact with enhancers to guide gene activity.

“We wanted to understand where Chd7 sits in the circuitry that specifies neural crest cell development and what is it driving or being driven by,” said Williams.

The discovery of the new enhancers was aided by two technologies, one that identifies regions of exposed DNA, and another that illustrates how the genome is organized in three dimensions. This allowed the team to “see” where and how different parts of the genome are communicating.