The polymorphic variant rs1800734 influences methylation acquisition and allele-specific TFAP4 binding in the MLH1 promoter leading to differential mRNA expression
| Autor: | Tim Maughan, Davide Trapani, Daniela Furlan, Ian Tomlinson, Hayley Davis, Rachael Thomas, Simon J. Leedham, Annabelle Lewis, Lily Goodyer-Sait, Connor Woolley, Marketa Tomkova, Ceres Fernandez-Rozadilla, Skirmantas Kriaucionis, Laura Chegwidden, Nora Sahnane, Claire Palles |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Databases
Factual lcsh:Medicine 0302 clinical medicine Gene expression Cancer genomics Cancer epigenetics lcsh:Science Promoter Regions Genetic Cancer genetics 0303 health sciences Multidisciplinary Functional genomics Methylation Chromatin 3. Good health DNA-Binding Proteins Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis DNA methylation Microsatellite Instability Colorectal Neoplasms MutL Protein Homolog 1 functional genomics congenital hereditary and neonatal diseases and abnormalities cancer genetics Biology MLH1 Polymorphism Single Nucleotide Article 03 medical and health sciences medicine Humans Genetic Predisposition to Disease RNA Messenger Allele Gene neoplasms Alleles 030304 developmental biology cancer genomics lcsh:R Microsatellite instability nutritional and metabolic diseases DNA Methylation medicine.disease digestive system diseases cancer epigenetics Case-Control Studies Cancer research chromatin lcsh:Q CpG Islands Transcription Factors |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-10 (2019) Thomas, R, Trapani, D, Goodyer-sait, L, Tomkova, M, Fernandez-rozadilla, C, Sahnane, N, Woolley, C, Davis, H, Chegwidden, L, Kriaucionis, S, Maughan, T, Leedham, S, Palles, C, Furlan, D, Tomlinson, I & Lewis, A 2019, ' The polymorphic variant rs1800734 influences methylation acquisition and allele-specific TFAP4 binding in the MLH1 promoter leading to differential mRNA expression ', Scientific Reports, vol. 9, no. 1 . https://doi.org/10.1038/s41598-019-49952-x |
| DOI: | 10.1038/s41598-019-49952-x |
| Popis: | The raw data is available on Mendeley at https://data.mendeley.com/datasets/hfpbctm7tg/draft?a=1c91e494-cadc-4be0-a8ff-91d8736a28e7 © The Author(s) 2019. Expression of the mismatch repair gene MutL homolog 1 (MLH1) is silenced in a clinically important subgroup of sporadic colorectal cancers. These cancers exhibit hypermutability with microsatellite instability (MSI) and differ from microsatellite-stable (MSS) colorectal cancers in both prognosis and response to therapies. Loss of MLH1 is usually due to epigenetic silencing with associated promoter methylation; coding somatic mutations rarely occur. Here we use the presence of a colorectal cancer (CRC) risk variant (rs1800734) within the MLH1 promoter to investigate the poorly understood mechanisms of MLH1 promoter methylation and loss of expression. We confirm the association of rs1800734 with MSI+ but not MSS cancer risk in our own data and by meta-analysis. Using sensitive allele-specific detection methods, we demonstrate that MLH1 is the target gene for rs1800734 mediated cancer risk. In normal colon tissue, small allele-specific differences exist only in MLH1 promoter methylation, but not gene expression. In contrast, allele-specific differences in both MLH1 methylation and expression are present in MSI+ cancers. We show that MLH1 transcriptional repression is dependent on DNA methylation and can be reversed by a methylation inhibitor. The rs1800734 allele influences the rate of methylation loss and amount of re-expression. The transcription factor TFAP4 binds to the rs1800734 region but with much weaker binding to the risk than the protective allele. TFAP4 binding is absent on both alleles when promoter methylation is present. Thus we propose that TFAP4 binding shields the protective rs1800734 allele of the MLH1 promoter from BRAF induced DNA methylation more effectively than the risk allele. Funding was provided by a Medical Research Council New Investigator Research Grant (MR/P000738/1). Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). D.T., N.S. and D.F. were supported by the EPIGENOMICS FLAGSHIP PROJECT- EPIGEN (project number 08934412) and by University of Insubria. M.T. and S.K. were funded by Ludwig Cancer Research. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|