Abstract 373: Spatial Expression Analysis of the Ischemic Heart Identifies Novel Factors Involved in Cardiac Remodeling and Disease
Cardiac ischemic injury is associated with expressional changes in a broad range of coding and non-coding genes. While genome-wide expression techniques like RNA sequencing, give valuable information about the transcriptional activity of genes, spatial clues are lost.
Here, we use a novel method (TomoSEQ) based on traditional histological techniques with low-input RNA sequencing to generate a spatial gene expression atlas for the infarcted heart. Transcriptome profiling of 50 consecutive sections from hearts exposed to ischemia reperfusion or sham surgery, allowed us to trace differential gene regulation throughout the infarct, borderzone and remote area. Fourteen days post-injury, we clearly observed differential expression curves specific for genes known to be relevant for cardiac function and disease, like Nppa (remodeling/hypertrophy), Col3a1 (fibrosis) and Atp2a2 (calcium handling), with the first two being more abundantly expressed in the infarct, and the latter more dominant towards the remote. Interestingly, the exact spatial information on these 3 reference genes enabled us to identify a set of genes that show an identical regulation, potentially linking these transcripts to the aforementioned biological function of the reference genes. The validity of using this method to identify genes that are expressionally linked was underscored by the observation that the correlation between the expression level of the Nppa, Col3a1, Atp2a2 and the newly identified genes could be confirmed in human cardiac tissue samples from patients suffering from ischemic heart disease. We next used an in silico approach to identify common transcription factors among the co-regulated genes. TomoSEQ analysis revealed a strong spatial correlation between these identified transcription factors and their target genes. This provides further support for our methodology, but also provides an opportunity to identify novel transcription factors relevant for cardiac function and disease.
Our study shows the power of spatial transcriptome profiling throughout the infarcted heart by giving local clues on changes in gene expression and allowing for the identification of novel genes and key transcription factors that could be relevant for cardiac repair upon injury.
Author Disclosures: G. Lacraz: None. J. Junker: None. K. Scholman: None. D. Versteeg: None. A. van Oudenaarden: None. E. van Rooij: None.
- © 2015 by American Heart Association, Inc.