VISTA Enhancer browser: an updated database of tissue-specific developmental enhancers

Abstract

Regulatory elements (enhancers) are major drivers of gene expression in mammals and harbor many genetic variants associated with human diseases. Here, we present an updated VISTA Enhancer Browser (https://enhancer.lbl.gov), a database of transgenic enhancer assays conducted in developing mouse embryos in vivo. Since the original publication in 2007, the database grew nearly 20-fold from 250 to over 4500 experiments and currently harbors over 23 500 images. The updated database provides structured information on experiments conducted at different stages of embryonic development, including enhancer activities of human pathogenic and synthetic variants and sequences derived from a variety of species. In addition to manually curated results of thousands of individual experiments, the new database also features hundreds of manually curated comparisons between alleles. The VISTA Enhancer Browser provides a crucial resource for study of human genetic variation, gene regulation and developmental biology.

Graphical Abstract

Figure 1.

Database organization and experimental workflow. (A) Structure of VISTA Enhancer Browser data. (B) Selection of putative enhancers and introduction of variants. Locus and element hierarchy levels. (C) Cloning of selected enhancer into a reporter construct, zygote injection and targeted integration (enSERT method). Experiment hierarchy level. (D) Results. E11.5 = embryonic stage E11.5.

Figure 2.

Genotyping. (A) Schematic of enSERT experimental workflow. (B) Interpretation of enSERT genotyping results.

Figure 3.

Experiment comparison. (A) Example of a manually curated comparison between alleles. Shown are the reference ZRS allele experiment (hs2496.0 sZH E11.5) and an experiment using single basepair ZRS mutation associated with polydactyly in hemimelic extra-toe mouse (hs2496.34 sZH E11.5). Introduction of the variant resulted in additional activity in the limb, as described in the boxed panel. Top panel is a fragment of Experiment page for reference experiment, bottom is a fragment of Experiment Comparison page. (B) Example of a side-by-side view of two experiments. The same element (hs271.0) was tested at two embryonic timepoints (E11.5 and E14.5). Similar forebrain-specific activity was observed at both timepoints.

Figure 4.

Database contents. (A) Distribution of experiments in terms of embryonic stage, promoter and transgenic method, organism from which the element was derived and the result of manual curation. ‘Comparative’ refers to experiments which were not curated individually, but only in relationship to other experiments (typically alleles). (B) Distribution of experiments that were curated positive in terms of tissue. (C) Correlation between tissues observed in the same experiment. n.s. = not significant (Fisher's Exact test, FDR ≥ 0.05). Blocks of similar tissues highlighted. DRG = dorsal root ganglia. facial mesen. = facial mesenchyme.