A Bayesian Approach for Analysis of Whole-Genome Bisulfite Sequencing Data Identifies Disease-Associated Changes in DNA Methylation

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Title: A Bayesian Approach for Analysis of Whole-Genome Bisulfite Sequencing Data Identifies Disease-Associated Changes in DNA Methylation
Author(s): Rackham, OJL
Langley, SR
Oates, T
Vradi, E
Harmston, N
Srivastava, PK
Behmoaras, J
Dellaportas, P
Bottolo, L
Petretto, E
Item Type: Journal Article
Abstract: DNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility remains to be fully understood. Here, we present a novel Bayesian smoothing approach (called ABBA) to detect differentially methylated regions (DMRs) from whole-genome bisulfite sequencing (WGBS). We also show how this approach can be leveraged to identify disease-associated changes in DNA methylation, suggesting mechanisms through which these alterations might affect disease. From a data modeling perspective, ABBA has the distinctive feature of automatically adapting to different correlation structures in CpG methylation levels across the genome while taking into account the distance between CpG sites as a covariate. Our simulation study shows that ABBA has greater power to detect DMRs than existing methods, providing an accurate identification of DMRs in the large majority of simulated cases. To empirically demonstrate the method’s efficacy in generating biological hypotheses, we performed WGBS of primary macrophages derived from an experimental rat system of glomerulonephritis and used ABBA to identify >1000 disease-associated DMRs. Investigation of these DMRs revealed differential DNA methylation localized to a 600 bp region in the promoter of the Ifitm3 gene. This was confirmed by ChIP-seq and RNA-seq analyses, showing differential transcription factor binding at the Ifitm3 promoter by JunD (an established determinant of glomerulonephritis), and a consistent change in Ifitm3 expression. Our ABBA analysis allowed us to propose a new role for Ifitm3 in the pathogenesis of glomerulonephritis via a mechanism involving promoter hypermethylation that is associated with Ifitm3 repression in the rat strain susceptible to glomerulonephritis.
Publication Date: 30-Mar-2017
Date of Acceptance: 3-Feb-2017
URI: http://hdl.handle.net/10044/1/47902
DOI: https://dx.doi.org/10.1534/genetics.116.195008
ISSN: 0016-6731
Publisher: GENETICS SOCIETY OF AMERICA
Start Page: 1443
End Page: 1458
Journal / Book Title: GENETICS
Volume: 205
Issue: 4
Copyright Statement: © 2017 Rackham et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Bayesian statistics
DNA methylation
WGBS
glomerulonephritis
SYSTEMIC-LUPUS-ERYTHEMATOSUS
MACROPHAGE ACTIVATION
CRESCENTIC GLOMERULONEPHRITIS
REGULATORY ELEMENTS
STATISTICAL-METHODS
GENE-EXPRESSION
REGIONS
MODEL
TRANSCRIPTION
INFERENCE
Bayesian statistics
DNA methylation
WGBS
glomerulonephritis
Animals
Bayes Theorem
DNA Methylation
Genome
Glomerulonephritis
High-Throughput Nucleotide Sequencing
Membrane Proteins
Promoter Regions, Genetic
Rats
Rats, Inbred Lew
Rats, Inbred WKY
Sensitivity and Specificity
Sequence Analysis, DNA
Developmental Biology
0604 Genetics
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine



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