PhD Candidate University of Colorado Boulder Arvada, Colorado, United States
Lindsey Broadwell (University of Colorado Boulder)| Michael Smallegan (University of Colorado Boulder)| Kevin Rigby (miRagen)| Massimo Buvoli (University of Colorado Boulder)| Jose Navarro-Arriola (University of Colorado Boulder)| Rusty Montgomery (miRagen)| John Rinn (University of Colorado Boulder)| Leslie Leinwand (University of Colorado Boulder)
Myosin heavy chain 7b (MYH7b) is annotated as an ancient gene that encodes a myosin II motor. A conserved exon-skipping mechanism prevents the expression of cardiac protein; however a long-noncoding RNA (lncMYH7b) and miRNA (miR-499) are expressed. While the roles of miR-499 in the heart are well-defined, it has been hypothesized that lncMYH7b RNA transcription is maintained to preserve miR-499 expression. Surprisingly, we have found that lncMYH7b plays an additional role in the cardiac transcriptome. In fact, lncMYH7b RNA knockdown in human iPS-derived cardiomyocytes triggers several changes in cardiac gene expression and function As an example, knockdown cells exhibited a slower beat rate and a significant reduction in sarcomere number. Potentially contributing to these phenotypes are decreased expression of adrenergic signaling proteins and the loss of formin homology 2 domain containing 3 protein (FHOD3), respectively. Perhaps most striking, as a result of knocking down lncMYH7b RNA, the important ratio of β- and α-myosin heavy chains was decreased at both the RNA and protein level. This is likely due to the loss of expression of TEAD3, a transcription factor known to target β-myosin in cardiomyocytes. Our data show that lncMYH7b RNA is a novel example of an ancient gene fulfilling different roles in the cell based on its alternative splicing. Furthermore, a shift in the myosin ratio is a molecular hallmark of heart failure, positioning this pathway as a therapeutic target for therapeutic intervention.