Detection of differentially methylated regions from whole-genome bisulfite sequencing data without replicates

Wu, Hao; Xu, Tianlei; Feng, Hao; Chen, Li; Li, Ben; Yao, Bing; Qin, Zhaohui S.; Jin, Peng; Conneely, Karen N.

doi:10.1093/nar/gkv715

Cited by 215 publications

(216 citation statements)

References 38 publications

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“…Sequencing data were aligned to the mm10 mouse genome using BSMAP2.74 33 . Differentially methylated regions (DMRs) were identified using Bioconductor package DSS 34 . We first performed statistical test of differentially methylated loci (DML) using DMLtest function (smoothing=TRUE) in DSS, the results were then used to detect differentially methylated regions using CallDMR function in DSS, with a p value threshold for calling DMR set at 0.01.…”

Section: Methodsmentioning

confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

380

350

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Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These resting memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogen, but also have many properties in common with naïve cells, including the ability to migrate to lymph nodes and spleen, and their pluri-potency. Thus, memory cells embody features of both naïve and effector cells, fueling a long-standing debate centered on whether memory T cells develop from effector cells or directly from naïve cells1–4. To better define the developmental path of memory CD8 T cells we investigated changes in DNA methylation programming at naïve and effector genes in virus specific CD8 T cells during acute LCMV infection of mice. Methylation profiling of effector CD8 T cell subsets at day 4 and 8 after infection showed that, rather than retaining a naïve epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naïve-associated genes and became demethylated at loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase, Dnmt3a, at an early stage of effector differentiation strikingly reduced methylation of naïve-associated genes and resulted in faster re-expression of these naïve genes, accelerating memory cell development. Longitudinal phenotypic and epigenetic characterization of virus-specific memory-precursor CD8 T cells transferred into antigen-free mice revealed that their differentiation into memory cells was coupled to cell-division independent erasure of de novo methylation programs and re-expression of naïve-associated genes. These data provide evidence that epigenetic repression of naïve-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells supporting a differentiation model where memory T cells arise from a subset of fate-permissive effector T cells.

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Section: Methodsmentioning

confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

380

350

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“…For RNA-seq data, CuffDiff software was used for statistical analysis of differentially expressed genes (q-value <0.05). DMRS were determined using the R software package DSS (Wu et al, 2015). A Wald test was performed at each CpG site to obtain P-values.…”

Section: Methodsmentioning

confidence: 99%

Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

et al. 2016

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SUMMARY DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that by 16 months of age, 65% of Dnmt3a+/− mice develop a CLL-like disease and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/− and Dnmt3aΔ/Δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene-expression analysis identified 26 hypomethylated and over-expressed genes common to both Dnmt3a+/− and Dnmt3aΔ/Δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.

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“…To compare individual HGSC DNA methylomes with FTE and OSE, we determined DMC for each HGSC using the R software package DSS (41), by smoothing the RnBeads normalized percent methylation values for 0.5kb units, and using a moving average algorithm. DMR were defined as regions of any length containing ≥ 3 CpGs and ≥ 25% methylation change.…”

Section: Methodsmentioning

confidence: 99%

DNA Methylome Analyses Implicate Fallopian Tube Epithelia as the Origin for High-Grade Serous Ovarian Cancer

Klinkebiel

Zhang

Akers

et al. 2016

Molecular Cancer Research

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High-grade serous ovarian cancer (HGSC) is the most common and lethal form of epithelial ovarian cancer (EOC). Two distinct tissues have been suggested as the tissue of origin: ovarian surface epithelia (OSE) and fallopian tube epithelia (FTE). We hypothesized that the DNA methylome of HGSC should more closely resemble the methylome of its tissue of origin. To this end, we profiled HGSC (n=10), and patient-matched OSE and FTE (n=5) primary fresh-frozen tissues, and analyzed the DNA methylome using Illumina 450K arrays (n=20) and Agilent Sure Select methyl-seq (n=7). Methylomes were compared using statistical analyses of differentially methylated CpG sites (DMC) and differentially methylated regions (DMR). In addition, methylation was evaluated within a variety of different genomic contexts, including CpG island shores and Homeobox (HOX) genes, due to their roles in tissue specification. Publically-available HGSC methylome data (n=628) were interrogated to provide additional comparisons with FTE and OSE for validation. These analyses revealed that HGSC and FTE methylomes are significantly and consistently more highly conserved than are HGSC and OSE. Pearson correlations and hierarchal clustering of genes, promoters, CpG islands, CpG island shores, and HOX genes all revealed increased relatedness of HGSC and FTE methylomes. Thus, these findings reveal that the landscape of FTE more closely resembles HGSC, the most common and deadly EOC subtype.

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Detection of differentially methylated regions from whole-genome bisulfite sequencing data without replicates

Cited by 215 publications

References 38 publications

Effector CD8 T cells dedifferentiate into long-lived memory cells

Effector CD8 T cells dedifferentiate into long-lived memory cells

Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

DNA Methylome Analyses Implicate Fallopian Tube Epithelia as the Origin for High-Grade Serous Ovarian Cancer

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