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Miragen, UT Southwestern Team Publishes Data Linking miR-15 to Cardiomyogenesis

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By Doug Macron

Researchers from Miragen Therapeutics and the University of Texas Southwestern Medical Center this week published data indicating that a specific microRNA, miR-15, can inhibit the production of new heart-muscle cells in mice.

The report adds to the body of evidence that Miragen and UT Southwestern researcher Eric Olson, who is a company co-founder, have generated suggesting the miRNA, as well as family member miR-195, may be targets for therapeutic intervention.

As reported by Gene Silencing News, Miragen and collaborators previously found that inhibition of miR-15 in mice could lower the number of cardiac cells killed during myocardial infarction while improving hypertrophy (GSN 1/29/2009).

Based on these and other findings, the company has begun developing a miR-15 antagonist as a treatment for post-myocardial infarction remodeling.

The latest findings, which appeared in Circulation Research, provide “a more robust understanding of miR-15's role in the inhibition of cell proliferation … [and] suggest that fine tuning of cardiac cell cycle genes by miRNAs may be an important regulatory component of heart regeneration and repair," Olson said in a statement.

In the paper, the investigators noted that mammalian cardiomyocytes withdraw from the cell cycle during early post-natal development, limiting the ability of the adult heart to regenerate after an injury. However, the regulatory mechanisms controlling the withdrawal process and binucleation are not well understood.

In order to identify miRNAs that might be involved in the “post-natal switch to terminal differentiation,” the team examined the expression patterns of cardiac miRNAs during transition toward binucleation and cell cycle withdrawal.

Microarray analysis revealed subsets of miRNAs that were either up- or down-regulated in mouse ventricles at one and 10 days of age, finding that miR-195 was the most highly over-expressed.

A collection of miRNAs that are dysregulated in the heart between post-natal days one and 10 were identified, with miR-195 proving to be the most highly up-regulated.

“Premature over-expression of miR-195 in the embryonic heart causes a spectrum of congenital heart abnormalities associated with premature cell cycle arrest,” they wrote, with the miRNA negatively regulating the expression of various cell cycle genes, including checkpoint kinase 1.

They also showed that inhibition of the miR-15 family in neonatal mice with locked nucleic acid-modified miRNA antagonists “was associated with an increased number of mitotic cardiomyocytes and de-repression of Chek1,” they wrote.

“This is the first study to implicate the miR-15 family in heart development,” the researchers concluded. “Of particular interest, over-expression of miR-195 in the developing heart is associated with a number
of congenital heart abnormalities, including ventricular septal defects and severe ventricular hypoplasia.”

Further, because the miR-15 family has been shown to lie downstream of the p53 tumor suppressor pathway, “it is tempting to speculate that the miR-15 family is an important downstream effector of a tumor suppressor network that is activated in the heart shortly after birth,” they added.

“Further analysis of the cis regulatory elements and upstream signals responsible for postnatal up-regulation of the miR-15 family may shed light on the molecular determinants of cardiomyocyte mitotic arrest and open new avenues to cardiomyocyte cell cycle reinduction for cardiac repair.”


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at dmacron [at] genomeweb [.] com

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