Functional genomics of chicken, mouse, and human titin supports splice diversity as an important mechanism for regulating biomechanics of striated muscle

Henk Granzier, Michael Radke, Joseph Royal, Yiming Wu, Thomas C. Irving, Michael Gotthardt, Siegfried Labeit

Research output: Contribution to journalReview article

25 Scopus citations

Abstract

Titin is a giant filamentous elastic protein that spans from the Z-disk to M-band regions of the sarcomere. The I-band region of titin is extensible and develops passive force in stretched sarcomeres. This force has been implicated as a factor involved in regulating cardiac contraction. To better understand the adaptation in the extensible region of titin, we report the sequence and annotation of the chicken and mouse titin genes and compare them to the human titin gene. Our results reveal a high degree of conservation within the genomic region encoding the A-band segment of titin, consistent with the structural similarity of vertebrate A-bands. In contrast, the genomic region encoding the Z-disk and I-band segments is highly divergent. This is most prominent within the central I-band segment, where chicken titin has fewer but larger PEVK exons (up to 1,992 bp). Furthermore, in mouse titin we found two LINE repeats that are inserted in the Z-disk and I-band regions, the regions that account for most of the splice isoform diversity. Transcript studies show that a group of 55 I-band exons is differentially expressed in chicken titin. Consistent with a large degree of titin isoform plasticity and variation in PEVK content, chicken skeletal titins range in size from ∼3,000 to ∼3,700 kDa and vary greatly in passive mechanical properties. Low-angle X-ray diffraction experiments reveal significant differences in myofilament lattice spacing that correlate with titin isoform expression. We conclude that titin splice diversity regulates structure and biomechanics of the sarcomere.

Original languageEnglish (US)
Pages (from-to)R557-R567
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume293
Issue number2
DOIs
StatePublished - Aug 2007

Keywords

  • Comparative genomics
  • Connectin
  • Exon-intron structure
  • Isoform expression

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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