Identification and validation of regulatory SNPs that modulate transcription factor chromatin binding and gene expression in prostate cancer

Jin, Hong; Jung, Su-Young; DebRoy, Auditi; Davuluri, Ramana V.

doi:10.18632/oncotarget.10520

Cited by 44 publications

(35 citation statements)

References 51 publications

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“…All of the genes with coding variants identified through the GWAS/post-GWAS approach have been included in our pathway analysis. The prominent consequence of non-coding functional variants included in this study [27,28] is mainly due to: i) change in TF binding site pattern [28,29], ii) change in DNA methylation marks [30] and iii) Chromatin architecture alteration [31], or a combination of these mechanisms.…”

Section: Materials and Methods: Prostate Cancer Risk Associated Functmentioning

confidence: 99%

Pathway analysis of genes identified through Post-GWAS to understand prostate cancer aetiology

Farashi¹,

Kryza²,

Batra³

2019

Preprint

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Understanding the role of risk regions identified by genome-wide association studies (GWAS) have made considerable progress lately referred to the post-GWAS era. Annotation of the genes to the GWAS and fine-mapped functional variants, and understanding their biological pathway/gene networks enrichments is expected to give rich dividend by elucidating the mechanisms underlying prostate cancer. To this aim, we compiled and analysed currently available post-GWAS data on genes identified through GWAS and validated through experimental studies in prostate cancer to investigate molecular biological pathways enriched for assigned functional genes. The results highlight some well-known cancer signalling pathways, antigen presentation process and enrichment in cell growth and development gene networks suggesting prostate cancer may result from the accumulation of the effects of functional variants through multiple gene sets and pathways. The upstream analysis identifies critical transcription factors, which supplements the results regarding the regulatory role of the post-GWAS genes. We also identified the common genes between post-GWAS and three well-annotated prostate cancer Oncomine data in patient samples in order to uncover possible main genes in prostate cancer development/progression. Post-GWAS generated knowledge of gene networks and pathways, if analysed further and targeted appropriately, will have an important impact on clinical management of the disease.

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Section: Materials and Methods: Prostate Cancer Risk Associated Functmentioning

confidence: 99%

Pathway analysis of genes identified through Post-GWAS to understand prostate cancer aetiology

Farashi¹,

Kryza²,

Batra³

2019

Preprint

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“…For example, while we identified 13 local-eQTLs linked to ntc in the infected condition, we are at this point unable to characterize their precise mode of action, preventing insights into the underlying regulatory mechanisms. To validate the effect of a particular variant on relevant genes, eQTL studies have so far often resorted to classical molecular biology techniques such as chromatin immunoprecipitation and small-scale reporter assays [58,59]. While the recent emergence of Massively Parallel Reporter Assays allows for a much more systematic analysis of the regulatory effect of variants in transcriptional elements [60][61][62], these assays are still unable to consider the complex interaction between genetic variation and gene expression.…”

Section: Large-scale In Vivo Local-eqtl Characterization Via Allelespmentioning

confidence: 99%

cis-regulatory variation modulates susceptibility to enteric infection in the Drosophila genetic reference panel

et al. 2020

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Background: Resistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. We have previously shown in the Drosophila Genetic Reference Panel (DGRP) that resistance to infection is highly heritable, but our understanding of how the effects of genetic variants affect different molecular mechanisms to determine gut immunocompetence is still limited. Results: To address this, we perform a systems genetics analysis of the gut transcriptomes from 38 DGRP lines that were orally infected with Pseudomonas entomophila. We identify a large number of condition-specific, expression quantitative trait loci (local-eQTLs) with infection-specific ones located in regions enriched for FOX transcription factor motifs. By assessing the allelic imbalance in the transcriptomes of 19 F1 hybrid lines from a large round robin design, we independently attribute a robust cis-regulatory effect to only 10% of these detected local-eQTLs. However, additional analyses indicate that many local-eQTLs may act in trans instead. Comparison of the transcriptomes of DGRP lines that were either susceptible or resistant to Pseudomonas entomophila infection reveals nutcracker as the only differentially expressed gene. Interestingly, we find that nutcracker is linked to infection-specific eQTLs that correlate with its expression level and to enteric infection susceptibility. Further regulatory analysis reveals one particular eQTL that significantly decreases the binding affinity for the repressor Broad, driving differential allele-specific nutcracker expression. Conclusions: Our collective findings point to a large number of infection-specific cis-and transacting eQTLs in the DGRP, including one common non-coding variant that lowers enteric infection susceptibility.

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“…В Японии полиморфизм rs62285902 гена NAALADL2 найден как маркер болезни Крона по данным полногеномного ассоциативного исследования [12]. Обнаружено, что гиперэкспрессия гена NAALADL2 при раке толстой кишки и простаты играет значимую роль в развитии и прогрессировании онкологического процесса [13]. Полиморфизм rs78943174 выявлен как ассоциированный с агрессивностью рака простаты, учитывавшийся по шкале Глисона [14].…”

Section: однонуклеотидныйunclassified

Association of single nucleotide polymorphisms rs7164665, rs71461059, rs74765750, rs6762529 with sudden cardiac death

et al. 2019

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Aim. To confirm the association between sudden cardiac death (SCD) and single nucleotide polymorphisms rs7164665, rs71461059, rs74765750, rs6762529, identified in own genome-wide associative study as new molecular genetic markers of SCD.Material and methods. As design we used case-control study. The SCD group was formed using the SCD criteria of the European Society of Cardiology (n=438, average age 53,2±9,1 years, male — 72,7%, women — 28,3%). The control group (n=435, average age 53,2±8,9 years, men — 70,0%, women — 30,0%) was selected by gender and age for the SCD group from the DNA bank of the international projects MONICA and HAPIEE. DNA was isolated by phenol-chloroform extraction from myocardial tissue in the SCD group and venous blood in the control group. Genotyping was performed by polymerase chain reaction followed by analysis of estriction fragment length polymorphism. The results are statistically processed using the SPSS 16.0 software package.Results. No carriers of the rare allele A of the single nucleotide polymorphism rs74765750 were found in the SCD group and the control group. No statistically significant differences were found between the SCD group and the control group relating to frequencies of genotypes and alleles of single nucleotide polymorphisms rs7164665 and rs71461059. In the age group older than 50 years, the proportion of carriers of the heterozygous CT genotype of the single nucleotide polymorphism rs6762529 in the SCD group is statistically significantly lower compared to the control group (CT vs CC+TT: OR=0,686, 95% CI 0,483-0,967 p=0,035).Conclusion. The CT genotype of the single nucleotide polymorphism rs6762529 is associated with a protective effect on SCD for people over 50 years of age. The association with single nucleotide polymorphisms rs7164665, rs71461059, rs74765750 with SCD has not been confirmed.

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Identification and validation of regulatory SNPs that modulate transcription factor chromatin binding and gene expression in prostate cancer

Cited by 44 publications

References 51 publications

Pathway analysis of genes identified through Post-GWAS to understand prostate cancer aetiology

Pathway analysis of genes identified through Post-GWAS to understand prostate cancer aetiology

cis-regulatory variation modulates susceptibility to enteric infection in the Drosophila genetic reference panel

Association of single nucleotide polymorphisms rs7164665, rs71461059, rs74765750, rs6762529 with sudden cardiac death

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