3D interactions with the growth hormone locus in cellular signalling and cancer-related pathways

in Journal of Molecular Endocrinology

Correspondence should be addressed to J K Perry or J M O’Sullivan: j.perry@auckland.ac.nz or justin.osullivan@auckland.ac.nz
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Growth hormone (GH) is a peptide hormone predominantly produced by the anterior pituitary and is essential for normal growth and metabolism. The GH locus contains five evolutionarily related genes under the control of an upstream locus control region that coordinates tissue-specific expression of these genes. Compromised GH signalling and genetic variation in these genes has been implicated in various disorders including cancer. We hypothesised that regulatory regions within the GH locus coordinate expression of a gene network that extends the impact of the GH locus control region. We used the CoDeS3D algorithm to analyse 529 common single nucleotide polymorphisms (SNPs) across the GH locus. This algorithm identifies colocalised Hi-C and eQTL associations to determine which SNPs are associated with a change in gene expression at loci that physically interact within the nucleus. One hundred and eighty-one common SNPs were identified that interacted with 292 eGenes across 48 different tissues. One hundred and forty-five eGenes were regulated in trans. eGenes were found to be enriched in GH/GHR-related cellular signalling pathways including MAPK, PI3K-AKT-mTOR, ERBB and insulin signalling, suggesting that these pathways may be co-regulated with GH signalling. Enrichment was also observed in the Wnt and Hippo signalling pathways and in pathways associated with hepatocellular, colorectal, breast and non-small cell lung carcinoma. Thirty-three eQTL SNPs identified in our study were found to be of regulatory importance in a genome-wide Survey of Regulatory Elements reporter screen. Our data suggest that the GH locus functions as a complex regulatory region that coordinates expression of numerous genes in cis and trans, many of which may be involved in modulating GH function in normal and disease states.

Supplementary Materials

    • Jain et al. Supplementary Figure 1: Correlation plot between SNP density across GH locus region and frequency of identified eGenes demonstrating that there was no correlation between them (R2=0.1).
    • Jain et al. Supplementary Figure 2: Correlation plot between number of samples present in GTEx per tissue and the number of cis-eQTLs in the respective tissue demonstrating a strong correlation between the two (R2=0.64).
    • Jain et al. Supplementary Figure 3: Distribution of topologically associating domain (TAD) structures with cis-eGenes (i.e. eGenes located <1 Mb from the SNP) and eGenes across chromosome 17 (both <1Mb and >1Mb apart from the SNPs). The Hi-C heat map was generated with the 3D Genome Browser using data from Rao et al42 for all the seven cell lines (GM12878, HMEC, KBM7, HUVEC, IMR90, K562 and NHEK). Tracks show TAD structures, the region containing the SNPs and identified eGenes. Blue and yellow bars represent different TAD regions.
    • Supplementary Data 1-a: List of common SNPs (dbSNP147) across GH gene locus (Chr17:62080000-61920000; GRCh37/hg19) used for analysis

 

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