3D interactions with the growth hormone locus in cellular signalling and cancer-related pathways
3D interactions with the growth hormone locus in cellular signalling and cancer-related pathways
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DOI：
10.1530/jme-20-0010
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发表时间：
2020-05-01
影响因子：
3.5
通讯作者：
Perry, Jo K.
中科院分区：
文献类型：
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作者：
Jain, Lekha;Fadason, Tayaza;Perry, Jo K.
生长激素(GH)是一种主要由垂体前叶分泌的多肽激素，对正常生长和代谢是必不可少的。生长激素基因座包含五个与进化相关的基因，受上游基因座控制区的控制，该控制区协调这些基因的组织特异性表达。生长激素信号受损和这些基因的遗传变异与包括癌症在内的各种疾病有关。我们假设生长激素基因控制区内的调节区协调基因网络的表达，该基因网络扩大了生长激素基因控制区的影响。我们使用CoDeS3D算法分析了生长激素基因座上的529个常见的单核苷酸多态(SNPs)。该算法识别共定位的Hi-C和eQTL关联，以确定哪些SNP与核内物理相互作用的基因座的基因表达变化有关。共鉴定出181个常见的SNP，它们与48个不同组织中的292个Egene相互作用。有145个Egene被反式调控。研究发现，与GH/GHR相关的细胞信号通路包括MAPK、PI3K-AKT-mTOR、ERBB和胰岛素信号通路都富含Egene，提示这些信号通路可能与GH信号通路共同调节。在Wnt和Hippo信号通路以及与肝细胞癌、结直肠癌、乳腺癌和非小细胞肺癌相关的通路中也观察到了富集性。在我们的研究中确定的33个eQTL SNP在全基因组调控元素调查报告筛查中被发现具有调控重要性。我们的数据表明，生长激素基因是一个复杂的调节区，协调许多顺式和反式基因的表达，其中许多基因可能参与调节正常和疾病状态下的生长激素功能。
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.