ABSTRACTMyosin heavy chain 7b (MYH7b) is an ancient member of the myosin heavy chain motor protein family that is expressed in striated muscles. In mammalian cardiac muscle, MYH7b RNA is expressed along with two other myosin heavy chains, β-myosin heavy chain (β-MyHC) and α-myosin heavy chain (a-MyHC). However, unlike β-MyHC and α-MyHC which are maintained in a careful balance at the protein level, the MYH7b locus does not produce protein in the heart due to a post-transcriptional exon-skipping mechanism that occurs in a tissue specific manner. Whether this locus has a role in the heart beyond producing its intronic microRNA, miR-499, was unclear. Using cardiomyocytes derived from human induced pluripotent stem cells as a model system, we have found that the non-coding exon skipped RNA (lncMYH7b) affects the transcriptional landscape of the human heart, independent of miR-499. Specifically, lncMYH7b regulates the ratio of β-MyHC to α-MyHC, which is crucial for heart function. This regulation is likely achieved through control of members of the TEA domain transcription factor family (TEAD1 and TEAD3). Therefore, we conclude that this ancient gene has been repurposed by alternative splicing to produce a regulatory long-noncoding RNA in the human heart that affects the myosin composition of the heart.
