BSMAP: whole genome bisulfite sequence MAPping program

Xi, Yuanxin; Li, Wei

doi:10.1186/1471-2105-10-232

Cited by 1,054 publications

(803 citation statements)

References 8 publications

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“…Raw sequencing reads were aligned against human genome version hg19/GRCh37 using BSMAP 42 . Custom Perl scripts were used to remove read pairs that aligned to different chromosomes.…”

Section: Methodsmentioning

confidence: 99%

Global delay in nascent strand DNA methylation

Charlton

Downing

Smith

et al. 2018

Nat Struct Mol Biol

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Cytosine methylation is widespread among organisms and essential for mammalian development. In line with early postulations of an epigenetic role in gene regulation, symmetric CpG methylation can be mitotically propagated over many generations with extraordinarily high fidelity. Here, we combine BrdU labeling and immunoprecipitation with genome-wide bisulfite sequencing to explore the inheritance of cytosine methylation onto newly replicated DNA in human cells. Globally, we observe a pronounced lag between the copying of genetic and epigenetic information that is reconsolidated within hours to accomplish faithful mitotic transmission. Populations of arrested cells show a global reduction of lag induced intermediate CpG methylation when compared to proliferating cells, while sites of transcription factor engagement appear cell-cycle invariant. Alternatively, the cancer cell line HCT116 preserves global epigenetic heterogeneity independently of cell-cycle arrest. Taken together, our data suggest that heterogeneous methylation largely reflects asynchronous proliferation, but is intrinsic to actively engaged cis-regulatory elements and cancer.

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“…Raw sequencing reads were aligned against human genome version hg19/GRCh37 using BSMAP 42 . Custom Perl scripts were used to remove read pairs that aligned to different chromosomes.…”

Section: Methodsmentioning

confidence: 99%

Global delay in nascent strand DNA methylation

Charlton

Downing

Smith

et al. 2018

Nat Struct Mol Biol

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“…In addition, alleles with incomplete bisulfite conversion may mimick hypermethylated alleles. Reduced sequence complexity, asymmetric C to T alignments, and increased searching space, compared to the original reference sequence, can result in false‐positive matches 37. To overcome these problems, we excluded all reads that showed incomplete bisulfite conversion at non‐CpG positions and all reads with low sequencing quality or sequencing errors.…”

Section: Discussionmentioning

confidence: 99%

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Böck

Appenzeller

Haertle

et al. 2018

Intl Journal of Cancer

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To evaluate the role of constitutive epigenetic changes in normal body cells of BRCA1/BRCA2‐mutation negative patients, we have developed a deep bisulfite sequencing assay targeting the promoter regions of 8 tumor suppressor (TS) genes (BRCA1, BRCA2, RAD51C, ATM, PTEN, TP53, MLH1, RB1) and the estrogene receptor gene (ESR1), which plays a role in tumor progression. We analyzed blood samples of two breast cancer (BC) cohorts with early onset (EO) and high risk (HR) for a heterozygous mutation, respectively, along with age‐matched controls. Methylation analysis of up to 50,000 individual DNA molecules per gene and sample allowed quantification of epimutations (alleles with >50% methylated CpGs), which are associated with epigenetic silencing. Compared to ESR1, which is representative for an average promoter, TS genes were characterized by a very low (< 1%) average methylation level and a very low mean epimutation rate (EMR; < 0.0001% to 0.1%). With exception of BRCA1, which showed an increased EMR in BC (0.31% vs. 0.06%), there was no significant difference between patients and controls. One of 36 HR BC patients exhibited a dramatically increased EMR (14.7%) in BRCA1, consistent with a disease‐causing epimutation. Approximately one third (15 of 44) EO BC patients exhibited increased rates of single CpG methylation errors in multiple TS genes. Both EO and HR BC patients exhibited global underexpression of blood TS genes. We propose that epigenetic abnormalities in normal body cells are indicative of disturbed mechanisms for maintaining low methylation and appropriate expression levels and may be associated with an increased BC risk.

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“…Sequencing was performed to yield >5x average coverage across the genome. Sequencing data were aligned to the mm10 mouse genome using BSMAP2.74 33 . Differentially methylated regions (DMRs) were identified using Bioconductor package DSS 34 .…”

Section: Methodsmentioning

confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

402

359

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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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BSMAP: whole genome bisulfite sequence MAPping program

Cited by 1,054 publications

References 8 publications

Global delay in nascent strand DNA methylation

Global delay in nascent strand DNA methylation

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Effector CD8 T cells dedifferentiate into long-lived memory cells

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