Cell Specificity of Human Regulatory Annotations and Their Genetic Effects on Gene Expression

Abstract

Epigenomic signatures from histone marks and transcription factor (TF)-binding sites have been used to annotate putative gene regulatory regions. However, a direct comparison of these diverse annotations is missing, and it is unclear how genetic variation within these annotations affects gene expression. Here, we compare five widely used annotations of active regulatory elements that represent high densities of one or more relevant epigenomic marks-"super" and "typical" (nonsuper) enhancers, stretch enhancers, high-occupancy target (HOT) regions, and broad domains-across the four matched human cell types for which they are available. We observe that stretch and super enhancers cover cell type-specific enhancer "chromatin states," whereas HOT regions and broad domains comprise more ubiquitous promoter states. Expression quantitative trait loci (eQTL) in stretch enhancers have significantly smaller effect sizes compared to those in HOT regions. Strikingly, chromatin accessibility QTL in stretch enhancers have significantly larger effect sizes compared to those in HOT regions. These observations suggest that stretch enhancers could harbor genetically primed chromatin to enable changes in TF binding, possibly to drive cell type-specific responses to environmental stimuli. Our results suggest that current eQTL studies are relatively underpowered or could lack the appropriate environmental context to detect genetic effects in the most cell type-specific "regulatory annotations," which likely contributes to infrequent colocalization of eQTL with genome-wide association study signals.

Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

“…Third, recent studies have shown that functionally constrained genes—which are depleted for missense or loss-of-function variants—are also less likely to have eQTLs, indicating uniform intolerance of both regulatory and coding variation 55 – 57 . Complementary studies focusing on regulatory elements have shown that large, cell-specific stretch enhancers harbor smaller effect size eQTLs than ubiquitous promoter regions 58 and that genes with more cognate enhancer sequence are depleted for eQTLs 57 . Our finding that islet eQTLs that map to the islet stretch enhancers most frequently implicated in GWAS regions had smaller eQTL effect sizes is consistent with these observations.…”

Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations

“…Independent support for this hypothesis comes from the observation that the effect sizes of significant eQTL SNPs mapping to HOT loci tend to be significantly lower (rho = −0.175, P < 5 × 10 −16 ) (Supplemental Fig. S8; Varshney et al 2019).…”

A transcription start site map in human pancreatic islets reveals functional regulatory signatures

“…Therefore, it is plausible that islet CAGE profiling from total RNA samples would comprise more stable promoter-associated RNA transcripts and have a lesser representation of weaker transcripts originating from enhancer regions. In our previous work (Varshney et al 2018), we showed that genetic variants in more cell type-specific enhancer regions have lower effects on gene expression than the variants occurring in more ubiquitous promoter regions. This aspect is in line with our observation that enhancer chromatin state regions comprise a lesser proportion of active transcription initiation sites and lower transcriptional activities relative to promoter state regions.…”