Myotonic Dystrophy Foundation

HOUSTON, TX (March 22, 1010) – Tiny slivers of genetic material called micro-RNAs regulate a critical event called alternative splicing in the immediate after-birth period that is crucial to proper development of the heart, said researchers at Baylor College of Medicine and the Chinese Academy of Sciences in Beijing in a report that appears in the current issue and on the cover page of the journal Genes and Development.

“In the first two to four weeks after birth, an infant’s heart undergoes dramatic remodeling to prepare for adult functional requirements,” said Dr. Thomas A. Cooper, a professor in the BCM departments of pathology and immunology and molecular and cellular biology at BCM. In the past, his group has shown that certain proteins – among them CUGBP1 and CUGBP2 – are part of a network that determines which proteins particular genes make. (CUGBP stands for CUG triplet repeat RNA binding protein).

Dr. Auinash Kalsotra, lead author on the study and a MDF funded post-doctoral fellow in the Cooper lab said, “Normally CUGBP1 and CUGBP2 proteins are high in the embryo but immediately decrease after birth. Because CUGBP1 controls alternative splicing of many genes in heart and skeletal muscle, its decrease after birth is part of a larger program to adapt to the normal adult function.” In their latest work, the researchers report on the coordinating role played by microRNAs in controlling CUGBP1 and CUGBP2 proteins. “CUGBP1 is aberrantly increased in myotonic dystrophy and this contributes to the pathological features of the disease because adult tissues start making embryonic proteins” said Kalsotra.

Micro-RNAs are very small pieces of single-stranded RNA no more than 20-25 nucleotides (the smallest structural component of genetic material) long. They bind to matching pieces of messenger mRNA, making it double-stranded. This reduces production of the corresponding protein. Kalsotra said “By deleting dicer (an essential gene for making all microRNAs) in adult heart we have uncovered a previously unknown link between these tiny bits of RNA and CUGBP1 and CUGBP2 proteins in heart.”

“This is part of a hierarchy of regulation,” said Cooper. “All of this happens on top of transcription” during which the information in the DNA is translated into RNA,which contains the instructions for making a protein. “Here we show how two different forms of post-transcriptional regulation control genes during heart development; changes in amounts of micro-RNAs control the proteins that then control alternative splicing.”

The micro-RNAs are up regulated (increased) and the splicing regulators (CUGBP1 and CUBP2) are down regulated (decreased),” Cooper said. “The increase in micro-RNAs causes the drop in CUGBP1 and CUBP2 proteins. During the three week period of development after birth, a micro-RNA called miR-23a/b increases and binds to the messenger RNA that codes for CUGBP1 and CUGBP2,”. The levels of those proteins decrease dramatically even though their levels of the messenger RNA stay the same. “The CUGBP proteins regulate splicing changes. When their levels decrease, this changes the expression of other proteins that are key to heart development”, said the researchers.

Dr. Cooper and Dr. Kalsotra anticipate doing further research on how disruption of this micro-RNA activity could affect diseases characterized by heart rhythm problems, such as myotonic dystrophy.

Others who took part in this research include Drs. Kun Wang and Pei-Feng Li of the Chinese Academy of Sciences in Beijing. Funding for this work came from the National Institutes of Health, the National Science Foundation and the Myotonic Dystrophy Foundation.

An abstract of the report can be found at http://genesdev.cshlp.org/

For more information on basic science research at Baylor College of Medicine, please go to: www.bcm.edu/news.

Posted with permission from Baylor College of Medicine.