Circadian regulation of myocardial sarcomeric Titin-cap (Tcap, telethonin)

Identification of cardiac clock-controlled genes using open access bioinformatics data

Peter S. Podobed, Faisal J. Alibhai, Chi Wing Chow, Tami A. Martino

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Circadian rhythms are important for healthy cardiovascular physiology and are regulated at the molecular level by a circadian clock mechanism. We and others previously demonstrated that 9-13% of the cardiac transcriptome is rhythmic over 24 h daily cycles; the heart is genetically a different organ day versus night. However, which rhythmic mRNAs are regulated by the circadian mechanism is not known. Here, we used open access bioinformatics databases to identify 94 transcripts with expression profiles characteristic of CLOCK and BMAL1 targeted genes, using the CircaDB website and JTK-Cycle. Moreover, 22 were highly expressed in the heart as determined by the BioGPS website. Furthermore, 5 heart-enriched genes had human/mouse conserved CLOCK:BMAL1 promoter binding sites (E-boxes), as determined by UCSC table browser, circadian mammalian promoter/enhancer database PEDB, and the European Bioinformatics Institute alignment tool (EMBOSS). Lastly, we validated findings by demonstrating that Titin cap (Tcap, telethonin ) was targeted by transcriptional activators CLOCK and BMAL1 by showing 1) Tcap mRNA and TCAP protein had a diurnal rhythm in murine heart; 2) cardiac Tcap mRNA was rhythmic in animals kept in constant darkness; 3) Tcap and control Per2 mRNA expression and cyclic amplitude were blunted in ClockΔ19/Δ19 hearts; 4) BMAL1 bound to the Tcap promoter by ChIP assay; 5) BMAL1 bound to Tcap promoter E-boxes by biotinylated oligonucleotide assay; and 6) CLOCK and BMAL1 induced tcap expression by luciferase reporter assay. Thus this study identifies circadian regulated genes in silico, with validation of Tcap, a critical regulator of cardiac Z-disc sarcomeric structure and function.

Original languageEnglish (US)
Article numbere104907
JournalPLoS One
Volume9
Issue number8
DOIs
StatePublished - Aug 14 2014

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Connectin
Bioinformatics
Computational Biology
bioinformatics
Clocks
Genes
heart
promoter regions
circadian rhythm
Assays
Messenger RNA
Circadian Rhythm
genes
Websites
assays
Cardiovascular Physiological Phenomena
Databases
Circadian Clocks
Darkness
mice

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Circadian regulation of myocardial sarcomeric Titin-cap (Tcap, telethonin) : Identification of cardiac clock-controlled genes using open access bioinformatics data. / Podobed, Peter S.; Alibhai, Faisal J.; Chow, Chi Wing; Martino, Tami A.

In: PLoS One, Vol. 9, No. 8, e104907, 14.08.2014.

Research output: Contribution to journalArticle

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