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The druggable genome and support for target identification and validation in drug development.

ABSTRACT: Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- and biomarker-associated loci from genome-wide association studies to an updated set of genes encoding druggable human proteins, to agents with bioactivity against these targets, and, where there were licensed drugs, to clinical indications. We used this set of genes to inform the design of a new genotyping array, which will enable association studies of druggable genes for drug target selection and validation in human disease.

SUBMITTER: Finan C

PROVIDER: S-EPMC6321762 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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The druggable genome and support for target identification and validation in drug development.

Finan Chris C Gaulton Anna A Kruger Felix A FA Lumbers R Thomas RT Shah Tina T Engmann Jorgen J Galver Luana L Kelley Ryan R Karlsson Anneli A Santos Rita R Overington John P JP Hingorani Aroon D AD Casas Juan P JP

Science translational medicine 20170301 383

Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- ...[more]

PMID: 28356508

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Project description:Cleft palate is among the most common structural birth defects in humans. Previous studies have shown that mutations in FOXF2 are associated with cleft palate in humans and mice and that Foxf2 acts in a Shh-Foxf-Fgf18-Shh molecular network controlling palatal shelf growth. In this study, we combined RNA-seq and ChIP-seq approaches to identify direct transcriptional target genes mediating Foxf2 function in palate development in mice. Of 155 genes that exhibited Foxf2-dependent expression in the developing palatal mesenchyme, 88 contained or were located next to Foxf2-binding sites. Through in situ hybridization analyses, we demonstrate that expression of many of these target genes, including multiple genes encoding transcription factors and several encoding extracellular matrix-modifying proteins, were specifically upregulated in the posterior region of palatal shelves in Foxf2-/- mouse embryos. Foxf2 occupancy at many of these putative target loci, including Fgf18, in the developing palatal tissues was verified by ChIP-polymerase chain reaction analyses. One of the Foxf2 target genes, Chst2, encodes a carbohydrate sulfotransferase integral to glycosaminoglycan sulfation. Correlating with ectopic Chst2 expression, Foxf2-/- embryos a exhibited region-specific increase in sulfated keratan sulfate and a concomitant reduction in chondroitin sulfate accumulation in the posterior palatal mesenchyme. However, expression of the core protein of versican, a major chondroitin sulfate proteoglycan important in palatal shelf morphogenesis, was increased, whereas expression of collagen I was reduced in the corresponding region of the palatal mesenchyme. These results indicate that, in addition to regulating palatal shelf growth through the Fgf18-Shh signaling network, Foxf2 controls palatal shelf morphogenesis through regulating expression of multiple transcription factors as well as through directly controlling the synthesis and processing of extracellular matrix components in the palatal mesenchyme. Our ChIP-seq and RNA-seq data sets provide an excellent resource for comprehensive understanding of the molecular network controlling palate development.

Dataset Information

The druggable genome and support for target identification and validation in drug development.

Publications

The druggable genome and support for target identification and validation in drug development.

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