Chromatin Architecture Around Stroke Haplotypes Provides Evidence that Genetic Risk is Conferred Through Vascular Cells

Abstract

Introduction: Genome-wide association studies (GWAS) have identified numerous stroke-associated SNPs. To understand how SNPs affect gene expression related to increased stroke risk, we studied epigenetic landscapes surrounding 26 common, validated stroke-associated loci. Methods: We mapped the SNPs to linkage disequilibrium (LD) blocks and examined H3K27ac, H3K4me1, H3K9ac, and H3K4me3 histone marks and transcription-factor binding-sites in pathologically relevant cell types (hematopoietic and vascular cells). Hi-C data were used to identify topologically associated domains (TADs) encompassing the LD blocks and overlapping genes. Results: Fibroblasts, smooth muscle, and endothelial cells showed significant enrichment for enhancer-associated marks within stroke-associated LD blocks. Genes within encompassing TADs reflected vessel homeostasis, cellular turnover, and enzymatic activity. Conclusions: Stroke-associated genetic variants confer risk predominantly through vascular cells rather than hematopoietic cell types.

Plain language summary

Previous studies have found several variations in the DNA sequence (known as single nucleotide polymorphisms) linked to higher stroke risk. But the mechanisms behind how they increase risk is unknown. One hypothesis is that they affect non-coding DNA elements (i.e., epigenetics), which in turn drive abnormal changes in gene expression leading to increased stroke risk. To investigate this potential mechanism, we mined publicly available, cell-type specific databases. We searched for overlap between the regions with polymorphisms and regions where DNA transcription machinery bind (i.e., enhancers, transcription factor binding sites). We found that fibroblasts and smooth muscle cells (cells in vessel walls) had more of these DNA elements in regions associated with stroke risk. Bioinformatics analyses of genes that could be affected by changes in these elements were linked to stroke-related mechanisms.

Keywords::

• epigenetic
• genetic risk
• histone marks
• stroke
• topologically-associated domain

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0307

Author Contributions

Conceptualization, VMT and KEP; methodology, VMT, JNJ, and KEP; software, VMT and KEP; validation, VMT and KEP; formal analysis, VMT, CCK, NA, and KEP; investigation, VMT, AHS, JNJ, and KEP; resources, VMT and AHS; data curation, VMT, HHR, MW, AHS, and KEP; writing-original draft preparation, VMT, CCK, and KEP; writing-review and editing, all authors; visualization, VMT and KEP; supervision, VMT and KEP; project administration, VMT and KEP; funding acquisition, VMT.

Financial&competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.