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Abstract 393: Cronos Titin in Human Heart Development

Titin is a giant myofibrillar protein that provides passive tension and facilitates sarcomere formation in striated muscle, where it spans from the Z-disk to the M-line. Recently, an alternative start site has been identified in the titin gene that is predicted to allow for expression of a novel isoform, Cronos, that is ~2/3 the size of full-length titin and lacks the Z-disk and most of the I-band domains. Because the start site for this isoform is spliced out of full-length titin transcripts, we are able to determine the expression levels of Cronos compared to full-length titin. Reverse-transcription followed by quantitative PCR using primers specific to this region indicate Cronos transcript levels are higher in human fetal ventricle and atrial tissue (days 90-105) than in adult samples, while full-length titin transcripts are higher in adult than fetal cardiac tissue. Additionally, human ventricular tissue stained with a custom antibody raised to recognize this specific region of Cronos titin indicated high levels of protein expression and integration into myofibrils in early fetal samples (days 54 and 81), while this novel isoform was nearly undetectable in later fetal (day 130) and adult tissue. The Cronos titin transcript and protein were also detected in high quantities in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which are believed to have a fetal level of maturity. Based on these data, we conclude that Cronos is predominantly a fetal isoform of titin. Future experiments will investigate the effects of a Cronos titin knockdown in hiPSC-CMs during and after differentiation to establish its functional role in human heart development.