The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression

Liu, Ning Qing; Huurne, Menno ter; Nguyen, Luan N.; Peng, Tianran; Wang, Shuang-Yin; Studd, James B.; Joshi, Onkar; Ongen, Halit; Bramsen, Jesper B.; Yan, Jian; Andersen, Claus Lindbjerg; Taipale, Jussi; Dermitzakis, Emmanouil T.; Houlston, Richard S.; Hubner, Nina C.; Stunnenberg, Hendrik G.

doi:10.1038/ncomms14418

Cited by 49 publications

(50 citation statements)

References 67 publications

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“…Previous studies have proven that AP4 could be a positive or negative regulator of tumour‐related genes by binding the E‐box of their promoters (Jackstadt et al ., ; Liu et al ., ). Here, we demonstrated that AP4 could bind within the LAPTM4B polymorphism region in vitro and in vivo and function as a positive transcriptional regulator.…”

Section: Discussionmentioning

confidence: 99%

AP4 positively regulates LAPTM4B to promote hepatocellular carcinoma growth and metastasis, while reducing chemotherapy sensitivity

Yue

Wang

et al. 2018

Molecular Oncology

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Polymorphisms of the lysosomal‐associated protein transmembrane‐4 beta (LAPTM4B) gene are related to various forms of tumour susceptibility, which led us to hypothesize that some unique transcription factors targeting this polymorphism region may affect the biological function of LAPTM4B in tumour progression. In this study, we found that the transcription factor AP4 directly binds to the polymorphism region of the LAPTM4B gene promoter and induces its transcription. In addition, we demonstrated that AP4 promotes hepatocellular carcinoma (HCC) cell proliferation and metastasis and depresses chemotherapy sensitivity via LAPTM4B by activating the PI3K/AKT signalling pathway and caspase‐dependent pathway. Interestingly, we found that AP4 could not only regulate LAPTM4B by directly binding to the promoter, but also be regulated via a positive feedback mechanism involving LAPTM4B acting on c‐myc. Finally, we showed that AP4 and LAPTM4B are highly coexpressed in HCC tissues, and their coexpression may be a marker of poor prognosis. These findings provide evidence of the expression and functional coupling between AP4 and LAPTM4B and shed light on the regulation of LAPTM4B and its function in liver cancer.

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Section: Discussionmentioning

confidence: 99%

AP4 positively regulates LAPTM4B to promote hepatocellular carcinoma growth and metastasis, while reducing chemotherapy sensitivity

Yue

Wang

et al. 2018

Molecular Oncology

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“…The high‐throughput chromosome conformation capture (Hi‐C) technique can be used to analyze the overall spatial conformation of chromosomes and investigate their physical properties at high resolution . It has been reported that the noncoding variants might affect distal target genes via long‐range loop formation . To validate the long‐range regulation between prioritized SNPs and RANKL , we downloaded Hi‐C or capture Hi‐C data on GM12878 and CD34 + cells from several studies, to query whether those genetics variants and RANKL were within the same chromatin interaction.…”

Section: Methodsmentioning

confidence: 99%

“…(34,35) It has been reported that the noncoding variants might affect distal target genes via long-range loop formation. (23,36) To validate the long-range regulation between prioritized SNPs and RANKL, we downloaded Hi-C or capture Hi-C data on GM12878 and CD34 þ cells from several studies, (37,38) to query whether those genetics variants and RANKL were within the same chromatin interaction. Topologically associating domains (TADs) are chromosomal regions within which DNA sequences most often establish long-range physical contact.…”

Section: Cis-expression Quantitative Trait Locus Analysismentioning

confidence: 99%

“…It is important to translate the SNPs associations into causal genes and biological pathways underlying the pathogenesis of osteoporosis. Recent studies have found that noncoding SNPs could regulate expressions of distal genes by long-range interactions, (17)(18)(19)(20)(21)(22)(23)(24) which provide us new insights into deciphering the relationship between noncoding SNPs and diseases.…”

Section: Introductionmentioning

confidence: 99%

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Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Zhu

Chen

et al. 2018

Journal of Bone and Mineral Research

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RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genomewide association studies (GWASs) have identified multiple intergenic single-nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (high-throughput chromosome conformation capture [Hi-C]), epigenetic annotation, and a series of functional assays. The eQTL analysis identified six potential functional SNPs (rs9533090, rs9594738, r8001611, rs9533094, rs9533095, and rs9594759) exclusively correlated with RANKL gene expression (p < 0.001) at 13q14.11. Co-localization analyses suggested that eQTL signal for RANKL and BMD-GWAS signal shared the same causal variants. Hi-C analysis and functional annotation further validated that the first five osteoporosis SNPs are located in a super-enhancer region to regulate the expression of RANKL via long-range chromosomal interaction. Particularly, dual-luciferase assay showed that the region harboring rs9533090 in the super-enhancer has the strongest enhancer activity, and rs9533090 is an allele-specific regulatory SNP. Furthermore, deletion of the region harboring rs9533090 using CRISPR/Cas9 genome editing significantly reduced RANKL expression in both mRNA level and protein level. Finally, we found that the rs9533090-C robustly recruits transcription factor NFIC, which efficiently elevates the enhancer activity and increases the RANKL expression. In summary, we provided a feasible method to identify regulatory noncoding SNPs to distally regulate their target gene underlying the pathogenesis of osteoporosis by using bioinformatics data analyses and experimental validation. Our findings would be a potential and promising therapeutic target for precision medicine in osteoporosis. © 2018 American Society for Bone and Mineral Research.

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“…The PCR plate has been utilized for genomic studies [29, 30], but has never been tested before for proteomic sample preparation. The plate tends to have appealing utilities in the sample preparation for multi-omics studies (e.g., genomics, transcriptomics, proteomics) [55, 56]. Overall, we believe the data present here will make the q96FASP approach much appealing for high throughput quantitative proteome analysis.…”

Section: Discussionmentioning

confidence: 88%

Quick 96FASP for high throughput quantitative proteome analysis

Bekele

Pieper

2017

Journal of Proteomics

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Filter aided sample preparation (FASP) is becoming a central method for proteomic sample cleanup and peptide generation prior to LC-MS analysis. We previously adapted this method to a 96-well filter plate, and applied to prepare protein digests from cell lysate and body fluid samples in a high throughput quantitative manner. While the 96FASP approach is scalable and can handle multiple samples simultaneously, two key advantages compared to single FASP, it is also time-consuming. The centrifugation-based liquid transfer on the filter plate takes 3~5 times longer than single filter. To address this limitation, we now present a quick 96FASP (named q96FASP) approach that, relying on the use of filter membranes with a large MWCO size (~30 kDa), significantly reduces centrifugal times. We show that q96FASP allows the generation of protein digests derived from whole cell lysates and body fluids in a quality similar to that of the single FASP method. Processing a sample in multiple wells in parallel, we observed excellent experimental repeatability by label-free quantitation approach. We conclude that the q96FASP approach promises to be a promising cost- and time-effective method for shotgun proteomics and will be particularly useful in large scale biomarker discovery studies.

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The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression

Cited by 49 publications

References 67 publications

AP4 positively regulates LAPTM4B to promote hepatocellular carcinoma growth and metastasis, while reducing chemotherapy sensitivity

AP4 positively regulates LAPTM4B to promote hepatocellular carcinoma growth and metastasis, while reducing chemotherapy sensitivity

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Quick 96FASP for high throughput quantitative proteome analysis

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