Close
Enter your
text here

How Does Modification of RNA Influence the Development of Pediatrics Dilated Cardiomyopathy?

How Does Modification of RNA Influence the Development of Pediatrics Dilated Cardiomyopathy? 1024 783 Abbie Miller

New study shows essential role of RNA methlytransferase-mediated m6A modification in regulating heart development.

Traditional research to understand the origins of congenital heart disease have focused on understanding how genetic mutations may cause heart problems. Now, a team at Nationwide Children’s Hospital is exploring a new way to understand congenital heart disease (CHD).

“How the body regulates gene activity after DNA is translated into RNA could have an important influence on the development of CHD,” says Jihyun Jang, PhD, principal investigator in the Center for Cardiovascular Research at Nationwide Children’s. “One of these regulatory processes involves a chemical modification called m6A, which controls how stable, translated and broken down the RNA is. We think that problems with this process may play a big role in pediatric dilated cardiomyopathy, a type of CHD where genetic mutations alone don’t explain everything.”

In a study recently published in Circulation, Dr. Jang’s team shows how a post-transcriptional process involving m6A regulates the maturation of sarcomeres in heart development. A sarcomere is the basic contractile unit of a muscle fiber, and appropriate development is essential for developing a strong, functioning heart.

Previous studies have shown that mutations in sarcomere-related genes are linked to pediatric dilated cardiomyopathy (DCM). Previous research has also shown that N6-methyl-adenosine (m6A) is an important influencer of mRNA metabolism. METTL3 and METTL14 proteins are the core components of the m6A methyltransferase complex.

Using mice with cardiomyocyte-specific deletions of genes Mettl3 and Mettl14, researchers investigated the role of the m6A methyltransferase complex in heart development.

“While genetic mutations in sarcomeric genes are well-established contributors to DCM, we observed that many cases lack clear post-transcriptional regulation. We hypothesized that m6A dysregulation could be an underappreciated mechanism in DCM pathogenesis,” says Dr. Jang.

Their results confirmed their hypothesis, showing that post-transcriptional regulation via m6A methylation is essential for proper sarcomere maturation and myocardial development. The loss of METTL3 and METTL14 led to severe cardiac defects, including DCM, in the genetically modified mouse model.

Notably, sarcomere-associated genes Mypn and Ttn were identified as direct targets of m6A modification, linking RNA methylation to the structural integrity of cardiomyocytes. This highlights a novel regulatory layer that could explain some cases of ​DCM and may provide new therapeutic targets, says Dr. Jang.

“Our next steps involve translating these findings into human models,” she adds. “We have already shown that METTL3 knockdown in human pluripotent stem cell-derived cardiomyocytes disrupts sarcomere maturation, mirroring our in vivo mouse results.”

Moving forward, Dr. Jang’s team plans to conduct more in-depth studies in human cardiac organoids to better understand how m6A dynamics regulate human heart development. Additionally, they aim to investigate whether specific m6A-binding proteins mediate the effects of m6A-modified sarcomere-related transcripts. These studies could pave the way for targeted therapies that modulate m6A levels in pediatric DCM and other CHDs.

This work was initiated in collaboration with Deqiang Li, MD, PhD, and further developed with the contributions of Vidu Garg, MD, and Jessie Yester, MD, PhD, in the Center for Cardiovascular Research at Nationwide Children’s.

 

Reference:

Hand SM, Zhai Y, Li D, Burke S, Lim H-W, Yester J, Garg V, Accornero F, Li X, Li D, Jang J. Loss of methyltransferase and hypomethylated m6A sarcomere transcripts leading to early-onset dilated cardiomyopathy. Circulation. 2025;151(23):1692-1695.

About the author

Abbie (Roth) Miller, MWC, is a passionate communicator of science. As the manager, medical and science content, at Nationwide Children’s Hospital, she shares stories about innovative research and discovery with audiences ranging from parents to preeminent researchers and leaders. Before coming to Nationwide Children’s, Abbie used her communication skills to engage audiences with a wide variety of science topics. She is a Medical Writer Certified®, credentialed by the American Medical Writers Association.

You might also like