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| Status |
Public on Oct 07, 2019 |
| Title |
KLF15-Wnt–Dependent Cardiac Reprograming Up-Regulates SHISA3 in the Mammalian Heart |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Sustained cardiac stress promotes the transition from an adaptive response to heart failure. Understanding of mechanisms governing this transition will assist in identifying targets that prevent this progression. Our study revealed age-specific transcriptional functions mediated by KLF15 that are crucial for cardiac homeostasis. We report that postnatally, KLF15 continuously activates cardiac metabolism, but represses pathological, hypertrophic pathways associated with cardiomyocyte de-differentiation and endothelial cell (EC) remodeling in an age-dependent manner. Our integrative genomic and transcriptomic analyses identified novel target genes directly bound, and either activated or repressed by KLF15 in vivo in the adult heart. We identified a cooperative program inducing aberrant EC remodeling, caused by a reduction of KLF15 and a concomitant activation of Wnt signaling. Within this program, we further identified a so far uncharacterized cardiac gene - Shisa3, which is expressed in the developing heart and is upregulated in cardiac hypertrophy, ischemia and failure. Importantly, we demonstrate that the KLF15- and Wnt co-dependent, SHISA regulation occurs also in the human myocardium. Altogether, our results unraveled and characterized a previously unknown cardiac gene Shisa3, and attributed its significance to EC homeostasis of the adult heart, controlled by KLF15-Wnt dynamics.
Purpose: The aim of this study was to compare transcriptome profiles (RNA-seq) of heart tissue with a WT or KO Klf15 locus at different murine ages - postnatal day10 (p10), 4-week-old and 20-week-old mice.
Methods: Cardiac tissue total RNA profiles for different groups were obtained using deep sequencing, in triplicates, using Illumina HiSeq4000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat, followed by DESeq2. qPCR validation was performed using TaqMan and SYBR Green assays.
Conclusions: Our study represents the first detailed analysis of the processes triggered upon Klf15 loss in hearts of different murine postnatal ages, which was so far not investigated. We report that this Klf15 loss first triggers Wnt canonical pathway activation, followed by activation of the non-canonical Wnt components, culminating in heart failure.
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| Overall design |
Gene expression profiling from cardiac ventricles of P10, 4-week-old and 20-week-old mice with Klf15 wild type and loss of function.
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| Contributor(s) |
Noack C, Iyer LM, Zelarayan LC |
| Citation(s) |
31582141 |
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| Submission date |
Apr 11, 2018 |
| Last update date |
Oct 07, 2019 |
| Contact name |
Laura C Zelarayan |
| E-mail(s) |
laura.zelarayan@med.uni-goettingen.de
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| Organization name |
University Medical Center, Goettingen
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| Department |
Institute of Pharmacology and Toxicology
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| Street address |
Robert-Koch Strasse 40
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| City |
Goettingen |
| State/province |
Lower Saxony |
| ZIP/Postal code |
37075 |
| Country |
Germany |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA449782 |
| SRA |
SRP139684 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE113027_DESeq2_normalized_counts.xlsx |
4.7 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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