Masonic Medical Research Institute publishes another major study uncovering key proteins that keep the heart beating properly

UTICA, NY - A groundbreaking new study led by researchers at the Masonic Medical Research Institute (MMRI) has identified that two closely related proteins, RBPMS and RBPMS2, act in tandem to protect the heart’s ability to process the genetic information needed for normal heart development and function.

This process, called splicing, edits a gene’s RNA by rearranging or skipping sections to create multiple versions of a protein from the same gene. This ensures that heart muscle cells produce the right proteins at the right time, to allow for normal heart function. Disruptions or mutations involved in this process cause cardiomyopathies and congenital heart diseases. While it has been suspected that splicing factors may cooperate, the functional importance of such a collaboration in the heart has remained unclear.

In a new research article published this week in Circulation Research — one of the world’s leading journals in cardiovascular science — Tongbin Wu, PhD, assistant professor of biomedical research and translational medicine at MMRI, discovered that RBPMS and RBPMS2 perform overlapping, but indispensable, roles in regulating gene splicing during heart development. Using advanced genetic models, the team found that removing both proteins from cardiomyocytes (heart muscle cells) proved embryonic lethal, causing severe structural defects in the heart’s contractile machinery. In contrast, removing either protein alone had little to no impact on survival or heart function.

“This study shows that splicing factors need to work together to safeguard and keep the heart functioning properly during development,” said Wu. “By working together, they ensure that genes critical for cardiac contraction are spliced correctly, preventing the kinds of errors that can lead to devastating heart disease.”

Through RNA sequencing and mechanistic experiments, the team uncovered that RBPMS and RBPMS2 not only promote heart-specific splicing programs, but that they also actively suppress non-cardiac genes, ensuring the heart maintains its unique molecular signature. Importantly, the study also demonstrates that the position of where these proteins bind to precursor messenger RNA determines whether they act as activators or repressors of splicing.

“These findings provide hope for the 40,000 children born each year in the United States with congenital heart disease, as well as the 1.1 million adults with dilated cardiomyopathy (DCM),” said Maria I. Kontaridis, Ph.D., executive director, Gordon K. Moe professor and chair of biomedical research and translational medicine at MMRI. “Understanding the cooperative network of these slicing factors opens the door to new therapeutic strategies- a testament to MMRI's position as a global leader in cardiovascular research."

The study, “RBPMS and RBPMS2 Cooperate to Safeguard Cardiac Splicing,” is available online in Circulation Research [DOI: 10.1161/CIRCRESAHA.125.326948].

This work was a collaboration between MMRI and the University of California San Diego (UCSD). MMRI scientists who contributed to the study include Tongbin Wu, Ph.D., Chao Gao, Ph.D., and Elise Stanley. UCSD researchers that are involved in this study include Zeyu Chen, Ph.D., Zengming Zhang, Ph.D., Yusu Gu, Ph.D., Xiaohai Zhou, Ph.D. and Ju Chen, Ph.D.

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About MMRI
MMRI is a leading biomedical research organization focused on advancing our understanding of human disease through basic and translational science. MMRI aims to develop innovative therapies for cardiovascular, neurocognitive, autoimmune, and rare diseases.

Photos included: Headshot of Tongbin Wu, Ph.D., and scientists in his laboratory.