Chromatin landscape and enhancer-gene interactiondifferences between three cardiac cell types

Anene Nzelu, C. G.; Zhu, Y.; Grenier, J.-C.; Poujol, R.; Koslowski, S.; Tastet, O.; Lee, C. J. M.; Ackers-Johnson, M. A.; Foo, R.; Hussin, J.

doi:10.1101/2025.09.23.678180

bioRxiv · 10.1101/2025.09.23.678180

Chromatin landscape and enhancer-gene interactiondifferences between three cardiac cell types

Anene Nzelu, C. G.·Zhu, Y.·Grenier, J.-C.·Poujol, R.·Koslowski, S.·Tastet, O.·Lee, C. J. M.·Ackers-Johnson, M. A.·Foo, R.·Hussin, J.

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Abstract

Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNP) associated with a specific traits and diseases, however, uncovering the true disease-relevant SNPs remains challenging. One limitation for prioritizing true disease-relevant SNPs from GWAS is that most of the identified SNPs are non-coding, making it difficult to unravel their mechanism of action. Nevertheless, mapping non-coding SNPs to enhancers is a validated approach to link SNPs to their target genes through the analysis of enhancer-gene interactions (EGI) and thus provide insight into their mechanism of action. While previous studies linking cardiac disease-relevant SNPs to enhancers and their target genes have focused on the principal cardiac cell type, cardiomyocytes (CMs), the analysis of other non-CM cell types has been largely ignored and has only gained attention recently. We hypothesize that characterizing cell-type-specific enhancer-gene interactions (EGIs) for these non-CMs, namely cardiac fibroblasts (CFs), endothelial cells (ECs), and smooth muscle cells (SMCs), followed by mapping cardiac-disease-associated non-coding SNPs to those enhancers will identify novel disease-relevant genes and provide insights for future mechanistic research. To identify the landscape of cell-type-specific EGIs in these cardiac cells, we have employed the activity-by-Contact (ABC) model. It integrates assay for transposase-accessible chromatin sequencing (ATAC-seq), H3K27ac chromatin immunoprecipitation with sequencing (ChIP-seq), and high-throughput chromosome conformation capture with H3K27ac immunoprecipitation (H3K27ac HiChIP) data to identify EGIs. We have identified the landscape of cell-type-specific EGIs in these cardiac cells. Furthermore, a higher similarity of the chromatin accessibility profile (ATAC-seq) between CF and SMC, compared to CF and EC, and SMC and EC was observed. Finally, overlapping identified EGIs with cardiac-disease-associated non-coding variants has allowed the identification of a QT-interval-associated SNP that is mapped to the enhancer region of an EC-specific EGI.

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Anene Nzelu, C. G., Zhu, Y., Grenier, J.-C., Poujol, R., Koslowski, S., Tastet, O., Lee, C. J. M., Ackers-Johnson, M. A., Foo, R., Hussin, J.. 2025-09-25. Chromatin landscape and enhancer-gene interactiondifferences between three cardiac cell types. https://doi.org/10.1101/2025.09.23.678180

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