The chromatin accessibility landscape of primary human cancers

Corces, M. Ryan; Granja, Jeffrey M.; Shams, Shadi; Louie, Brent; Seoane, José A.; Zhou, Wanding; Silva, Tiago C.; Groeneveld, Clarice S.; Wong, Christopher; Cho, Seung Woo; Satpathy, Ansuman T.; Mumbach, Maxwell R.; Hoadley, Katherine A.; Robertson, A. Gordon; Sheffield, Nathan C.; Felau, Ina; Castro, Mauro A. A.; Berman, Benjamin P.; Staudt, Louis M.; Zenklusen, Jean C.; Laird, Peter W.; Curtis, Christina; Greenleaf, William J.; Chang, Howard Y.

doi:10.1126/science.aav1898

Cited by 882 publications

(1,198 citation statements)

References 78 publications

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“…To further validate the SALP-seq results, we also compared the peaks enriched in 11 EC cfDNA samples with a recently published ATAC-seq data of 19 EC tissues derived from donors with diverse demographic features. 33 The results indicated that the peaks enriched in 11 EC cfDNA samples had low percentage of overlap with the EC-specific peaks identified by ATACseq (Supporting Information Fig. S6A).…”

Section: Characterization Of Chromatin State With Cfdnamentioning

confidence: 94%

Decoding genetic and epigenetic information embedded in cell free DNA with adapted SALP‐seq

Dai

et al. 2019

Intl Journal of Cancer

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Cell free DNA (cfDNA) in human plasma carries abundant information, which has therefore been the key sample for noninvasive prenatal testing (NIPT) and liquid biopsy. Especially by using the rapidly developed next‐generation sequencing (NGS) techniques, the genetic and epigenetic information embedded in cfDNA has been effectively and extensively decoded. In this process, a key step is to construct the NGS library. Due to its high degradation, the single strand‐based method was reported to be more qualified to construct the NGS library of cfDNA. In order to develop a new simple method for this application, this study adapted our recently developed single strand adaptor library preparation (SALP) method for constructing an NGS library of cfDNA. In the improved method, cfDNA was firstly denatured into single strands and then ligated with a single strand adaptor (SSA) that had a 3′ overhang of 3 random bases by using T4 DNA ligase. The SSA‐ligated DNA was converted into double‐stranded DNA with an additional adenine at the other end by polymerizing with Taq polymerase. Next, a barcode T adaptor (BTA) was ligated to this end. Finally, the cfDNA ligated with two adaptors was amplified with the Illumina‐compatible primers for NGS. Using the method, this study successfully sequenced 20 cfDNA samples from 16 esophageal cancer patients and 4 healthy people. By bioinformatics analysis, this study found the genetic and epigenetic difference between patients and healthy people and identified 23 epigenetic and 28 genetic altered esophageal cancer‐specific genes.

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Section: Characterization Of Chromatin State With Cfdnamentioning

confidence: 94%

Decoding genetic and epigenetic information embedded in cell free DNA with adapted SALP‐seq

Dai

et al. 2019

Intl Journal of Cancer

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“…Recognizing that the variable sequencing depths for the datasets may lead to biases in the number of summits, we sought to obtain peaks with similar levels of evidence. To achieve this, we employed a method used by The Cancer Genome Atlas (Corces et al 2018) (See Methods). We then added 250 base pairs (bp) to either side of each summit and the uniform peaks were merged within each population.…”

Section: A Uniform Pipeline For Processing Of Mouse Atac-seq Datamentioning

confidence: 99%

“…Since we were comparing ATAC-seq datasets with vastly different sequencing depths and numbers of called summits, we applied a recently introduced filtering strategy for ATAC-seq peaks (Corces et al 2018). For each dataset, we summed the MACS2 peak scores and divided that number by one million (total score per million).…”

Section: G G T C C G C G T T C G C G C C Cmentioning

confidence: 99%

“…For each dataset, we summed the MACS2 peak scores and divided that number by one million (total score per million). We then divided each individual peak score by the total score per million for that dataset to produce a "score per million" (Corces et al 2018). Ultimately we chose a "score per million" cutoff of two as that would equate to a P-value per million of 0.01.…”

Section: G G T C C G C G T T C G C G C C Cmentioning

confidence: 99%

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Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Hook

McCallion

2018

Preprint

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Genome-wide association studies have implicated thousands of non-coding variants across human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in discrete cortical layer V excitatory neurons. We also show differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in layers II-III, IV, V as well as the dentate gyrus. Finally, we use these data to fine-map variants in 177 schizophrenia loci, nominating variants in 104/177 loci, and place them in the cellular context where they may modulate risk.

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“…A major mechanism of regulatory variants is alternation of chromatin accessibility to TFs (5,28). We thus mapped TF-binding site (TFBS) footprints from ATAC-seq data and examined their enrichment of ASoC SNPs (Methods).…”

Section: Main Textmentioning

confidence: 99%

Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants

Zhang

Qiao

et al. 2019

Preprint

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Functional interpretation of noncoding disease variants, which likely regulate gene expression, has been challenging. Chromatin accessibility strongly influences gene expression during neurodevelopment; however, to what extent genetic variants can alter chromatin accessibility in the context of brain disorders/traits is unknown. Using human induced pluripotent stem cell (iPSC)-derived neurons as a neurodevelopmental model, we identified abundant open-chromatin regions absent in adult brain samples and thousands of genetic variants exhibiting allele-specific open-chromatin (ASoC). ASoC variants are overrepresented in brain enhancers, transcription-factor-binding sites, and quantitative-trait-loci associated with gene expression, histone modification, and DNA methylation. Notably, compared to open chromatin regions and other commonly used functional annotations, neuronal ASoC variants showed much stronger enrichments of risk variants for various brain disorders/traits. Our study provides the first snapshot of the neuronal ASoC landscape and a powerful framework for prioritizing functional disease variants.One Sentence SummaryAllele-specific open chromatin informs functional disease variants

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The chromatin accessibility landscape of primary human cancers

Cited by 882 publications

References 78 publications

Decoding genetic and epigenetic information embedded in cell free DNA with adapted SALP‐seq

Decoding genetic and epigenetic information embedded in cell free DNA with adapted SALP‐seq

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants

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