DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML

Lund, K., Cole, J., VanderKraats, N. D., McBryan, T., Pchelintsev, N. A., Clark, W., Copland, M. , Edwards, J. R. and Adams, P. (2014) DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML. Genome Biology, 15(7), p. 406. (doi:10.1186/s13059-014-0406-2)

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Publisher's URL: http://dx.doi.org/10.1186/s13059-014-0406-2

Abstract

<b>Background</b>. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors (DNMTi), 5-azacytidine (AzaC) and 5-aza-2’-deoxycytidine (Decitabine), benefit some MDS/AML patients. However, the role of DNMTi-induced DNA hypomethylation in regulation of gene expression in AML is unclear.<p></p> <b>Results. </b> We compared the effects of AzaC on DNA methylation and gene expression using whole-genome single-nucleotide bisulfite-sequencing (WGBS) and RNA-sequencing in OCI-AML3 (AML3) cells. For data analysis, we used an approach recently developed for discovery of differential patterns of DNA methylation associated with changes in gene expression, that is tailored to single-nucleotide bisulfite-sequencing data (Washington University Interpolated Methylation Signatures (WIMSi)). By this approach, a subset of genes upregulated by AzaC was found to be characterized by AzaC-induced signature methylation loss flanking the transcription start site. These genes are enriched for genes increased in methylation and decreased in expression in AML3 cells compared to normal hematopoietic stem and progenitor cells. Moreover, these genes are preferentially upregulated by Decitabine in human primary AML blasts, and control cell proliferation, death and development. <p></p> <b>Conclusions.</b> Our WGBS and WIMSi data analysis approach has identified a set of genes whose is methylation and silencing in AML is reversed by DNMTi. These genes are good candidates for direct regulation by DNMTi, and their reactivation by DNMTi may contribute to therapeutic activity. This study also demonstrates the ability of WIMSi to reveal relationships between DNA methylation and gene expression, based on single-nucleotide bisulfite-sequencing and RNA-seq data.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cole, Mr John and Clark, Mr William and Adams, Professor Peter and Pchelintsev, Dr Nikolay and Copland, Professor Mhairi and McBryan, Dr Anthony
Authors: Lund, K., Cole, J., VanderKraats, N. D., McBryan, T., Pchelintsev, N. A., Clark, W., Copland, M., Edwards, J. R., and Adams, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Genome Biology
Publisher:BioMed Central
ISSN:1465-6906
ISSN (Online):1465-6914
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Genome Biology 15(7):406
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
506531An investigation of the control of cell division and quiescence in leukaemic versus normal haemopoietic stem and progenitor cellsMhairi CoplandScottish Executive Health Department (SEHHD-CSO)SCD/04RI CANCER SCIENCES