Abstract
Existing studies of chromatin conformation have primarily focused on potential enhancers interacting with gene promoters. By contrast, the interactivity of promoters per se, while equally critical to understanding transcriptional control, has been largely unexplored, particularly in a cell type-specific manner for blood lineage cell types. In this study, we leverage promoter capture Hi-C data across a compendium of blood lineage cell types to identify and characterize cell type-specific super-interactive promoters (SIPs). Notably, promoter-interacting regions (PIRs) of SIPs are more likely to overlap with cell type-specific ATAC-seq peaks and GWAS variants for relevant blood cell traits than PIRs of non-SIPs. Moreover, PIRs of cell-type-specific SIPs show enriched heritability of relevant blood cell trait (s), and are more enriched with GWAS variants associated with blood cell traits compared to PIRs of non-SIPs. Further, SIP genes tend to express at a higher level in the corresponding cell type. Importantly, SIP subnetworks incorporating cell-type-specific SIPs and ATAC-seq peaks help interpret GWAS variants. Examples include GWAS variants associated with platelet count near the megakaryocyte SIP gene EPHB3 and variants associated lymphocyte count near the native CD4 T-Cell SIP gene ETS1. Interestingly, around 25.7% ~ 39.6% blood cell traits GWAS variants residing in SIP PIR regions disrupt transcription factor binding motifs. Importantly, our analysis shows the potential of using promoter-centric analyses of chromatin spatial organization data to identify biologically important genes and their regulatory regions.
Highlights
Genome-wide chromosome conformation capture techniques such as Hi-C [1] have been widely used to study chromatin three-dimensional (3D) organization
We find that the latter seems to be the norm. This finding sheds light regarding the formation of super-interactive promoters (SIPs): to ensure the expression level of some critical gene, multiple regulatory regions are likely key for orchestrating fine transcriptional control
We find that a small number of promoter baits (~7.5%) have extremely high cumulative interaction scores, as defined based on the curve inflection point in each cell type, and annotated them as super-interactive promoters (SIPs)
Summary
Genome-wide chromosome conformation capture techniques such as Hi-C [1] have been widely used to study chromatin three-dimensional (3D) organization. Chromatin spatial organization studies have largely focused on regulatory regions, but characterization of the 3D genome at promoters is important for understanding gene expression regulation. To bridge this gap, capture Hi-C and subsequent variations were developed as an extension of the Hi-C technique by combining target enrichment and sequencing [5,6,7,8]. Capture Hi-C and subsequent variations were developed as an extension of the Hi-C technique by combining target enrichment and sequencing [5,6,7,8] One such capture technique, promoter capture Hi-C (pcHi-C), was developed to focus on promoter regions. PcHi-C enables genome-wide detection of distal promoterinteracting regions (PIRs) for all promoters with a priori designed probes/baits in a single
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