metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data

Jühling, Frank; Kretzmer, Helene; Bernhart, Stephan H.; Otto, Christian; Stadler, Peter F.; Hoffmann, Steve

doi:10.1101/gr.196394.115

Cited by 360 publications

(303 citation statements)

References 26 publications

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“…We next used established methods (Jühling et al, 2016) to identify differentially methylated regions (DMRs) between the TRBS patient and his sibling using all three peripheral blood cell populations. This analysis identified 4,054 DMRs with >10 CpGs and a mean methylation difference >0.2 (FDR<0.05; Figure 1D), which encompassed only 0.45% of all CpGs.…”

Section: Resultsmentioning

confidence: 99%

“…Identification of differentially methylated regions (DMRs). The program ‘metilene’ (Jühling et al, 2016) was used to analyze the raw methylation ratios at all CpGs to identify differentially methylated regions (DMRs) with >10 CpGs and a mean methylation difference between the same groups of >0.2. DMRs were filtered to retain those with FDR <0.05, and adjacent DMRs <50bp apart were merged.…”

Section: Methods and Resourcesmentioning

confidence: 99%

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CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

Spencer

Russler‐Germain

Ketkar

et al. 2017

Cell

188

193

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Summary DNMT3A mutations occur in ~25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3AR882H, has dominant negative activity that reduces DNA methylation activity by ~80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3AR882 mutations. Non-leukemic hematopoietic cells with DNMT3AR882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing, and was essentially absent in AMLs with DNMT3AR882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3AR882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.

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Section: Resultsmentioning

confidence: 99%

Section: Methods and Resourcesmentioning

confidence: 99%

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

Spencer

Russler‐Germain

Ketkar

et al. 2017

Cell

188

193

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show abstract

“…Libraries for DNA methylation were prepared using the SeqCap Epi System (Roche, Basel, Switzerland) and sequenced on the Illumina HiSeq 4000. Reads were aligned to GRCh38 using Bowtie 2 [23], DNA methylation ratios for CpGs were called by Bismark [24], and differentially methylated regions (DMRs) were identified using Metilene [25]. Gene set enrichment analysis was performed on lists of DMR-associated genes using WebGestalt [22].…”

Section: Genome-wide Targeted-capture Dna Methylation Sequencingmentioning

confidence: 99%

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

Zhang

et al. 2019

Preprint

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Heterozygous deletions in the 15q13.3 region are associated with several neuropsychiatric disorders including autism, schizophrenia, and attention deficit hyperactivity disorder. Several genes within the 15q13.3 deletion region may play a role in neuronal dysfunction, based on association studies in humans and functional studies in mice, but the intermediate molecular mechanisms remain unknown.We analyzed the genome-wide effects of the 15q13.3 microdeletion on the transcriptome and epigenome. Induced pluripotent stem cell (iPSC) lines from three patients with the typical heterozygous 15q13.3 microdeletion and three sex-matched controls were generated and converted into induced neurons (iNs) using the neurogenin-2 induction method. We analyzed genome-wide gene expression using RNA-Seq, genome-wide DNA methylation using SeqCap-Epi, and genome-wide chromatin accessibility using ATAC-Seq, in both iPSCs and iNs. In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the deletion on the transcriptome and epigenome, with the effects being cell type specific and occurring at discrete loci. Several genes and pathways associated with neuropsychiatric disorders and neuronal development were significantly altered, including Wnt signaling, ribosome biogenesis, DNA binding, and clustered protocadherins. This molecular systems analysis of a large neuropsychiatric microdeletion can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders. IntroductionThe neuropsychiatric 15q13.3 microdeletion (OMIM 612001) is a heterozygous deletion of approximately 1.5-2 Mb at coordinates 30.5 Mb to 32.5 Mb on chromosome 15 (hg19) [1]. The deletion breakpoints lie within two regions of segmental duplications, which likely mediate the creation of the recurrent microdeletion via non-allelic homologous recombination [2]. The 15q13.3 microdeletion has an estimated prevalence of 1 in 40,000 individuals, and was first reported in 2008, in nine individuals with mental retardation, seizures, and mild facial dysmorphism [3]. Since then, several other phenotypes have been associated with this copy number variant (CNV), including autism spectrum disorder, schizophrenia, mood disorders, attention deficit hyperactivity disorder, hypotonia, and cardiac defects [1,4,5].The most common form of the 15q13.3 microdeletion, which is the subject of our study, results in the heterozygous loss of seven protein-coding genes (CHRNA7, FAN1, TRPM1, KLF13, OTUD7A, MTMR10, ARHGAP11B) and one microRNA (MIR211) [4]. Several of these genes have previously been investigated as candidates for having a role in the neuropsychiatric symptoms associated with the CNV. The most frequently proposed candidate gene is C...

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“…Methylation ratios were obtained using the methratio.py script. The program "metilene" (45) was used to analyze the raw methylation ratios at all CpGs to identify DMRs with more than 10 CpGs and a mean methylation difference between the same groups of more than 0.2. DMRs were filtered to retain those with an FDR of less than 0.05, and adjacent DMRs less than 50 bp apart were merged.…”

Section: Table 2 Mutagenesis and C-terminal Tag Cloning Primer Sequementioning

confidence: 99%

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

Cole

Russler‐Germain

Ketkar

et al. 2017

Journal of Clinical Investigation

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metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data

Cited by 360 publications

References 26 publications

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

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