MicroRNA let-7 is a key regulator of heart maturation
Biochemistry, University of Washington
June 4, 2015
Foege N130A, Wallace H. Coulter Seminar Room
Many heart diseases are manifested as late onset heart defects, during cardiomyocyte postnatal maturation. However, human cardiomyocyte maturation is poorly understood process at the moment. Using large scale profiling methods, we showed that the molecular signatures in in-vitro matured hESC derived cardiomyocytes are similar to those seen in the in-vivo derived mature cardiac tissues, thus enabling them to be used as excellent model to identify the metabolites and microRNAs that accelerate human cardiac maturation. We have now identified a key microRNA, let-7 that acts as a molecular switch, essential for human embryonic heart cells to grow into more mature, adult-like cardiomyocytes. let-7 upregulation can accelerate maturation; the cardiomyocytes switch to a fatty acid-based metabolism and become larger, stronger, and structurally and functionally more mature. We dissected the mechanism of let-7 function in maturation and found that in addition to its effect on the insulin pathway, the let-7 microRNA drives the metabolic and functional changes by repressing the histone methyltransferase, EZH2 that affects the expression of a wide variety of genes, including those involved in fatty acid metabolism. These results indicate let-7 as an important mediator in augmenting metabolic energetics in maturing cardiomyocytes. Our goal now is to generate a microRNA cocktail to understand and manipulate the postnatal maturation of human embryonic stem cell derived cardiomyocytes.
Dr. Hannele Ruohola-Baker is a Professor in the Department of Biochemistry at the University of Washington. She earned her Ph.D. degree in Cell Biology from the University of Helsinki/Yale University at 1989 and subsequently received her post-doctoral training at the Howard Hughes Medical Institute within the University of California, San Francisco at 1993. Her laboratory studies the molecules and cellular properties that are required for stem cell states and their differentiation capacity, both in normal and pathological situations. During the recent years her group has shown that microRNAs and the HIF pathway play key roles in regulating adult and embryonic stem cell self-renewal in model organisms as well as in human embryonic stem cells. During her career, she has been an inventor of multiple patents and the recipient of numerous awards, including the Undergraduate Mentor Award, Tietze Award, Pew Award, Basil O’Connor Award and American Heart Association Established Investigator award.