Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer

Dâ2Antonio, Matteo; Weghorn, Donate; Dâ2Antonio-Chronowska, Agnieszka; Coulet, Florence; Olson, K.M.; DeBoever, Christopher; Drees, Frauke; Arias, Angelo; Alakus, Hakan; Richardson, Andrea L.; Schwab, Richard B.; Farley, Emma K.; Frazer, Kelly A.

doi:10.1038/s41467-017-00100-x

Cited by 23 publications

(17 citation statements)

References 76 publications

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“…The whole genome was divided into 200-bp bins and the bins with similar sequence characteristics (and thus similar mutation rates) were clustered together using four covariates (D’Antonio et al, 2017; Lawrence et al, 2013): 1) DNA replication timing; 2) open vs. closed chromatin status; 3) guanine and cytosine (GC) content; and 4) gene density in the 500 kb surrounding each bin. The values of all covariates were normalized to have mean = 0 and standard deviation = 1.…”

Section: Methodsmentioning

confidence: 99%

Insights into the Mutational Burden of Human Induced Pluripotent Stem Cells from an Integrative Multi-Omics Approach

et al. 2018

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To understand the mutational burden of human induced pluripotent stem cells (iPSCs), we sequenced genomes of 18 fibroblast-derived iPSC lines and identified different classes of somatic mutations based on structure, origin, and frequency. Copy-number alterations affected 295 kb in each sample and strongly impacted gene expression. UV-damage mutations were present in ∼45% of the iPSCs and accounted for most of the observed heterogeneity in mutation rates across lines. Subclonal mutations (not present in all iPSCs within a line) composed 10% of point mutations and, compared with clonal variants, showed an enrichment in active promoters and increased association with altered gene expression. Our study shows that, by combining WGS, transcriptome, and epigenome data, we can understand the mutational burden of each iPSC line on an individual basis and suggests that this information could be used to prioritize iPSC lines for models of specific human diseases and/or transplantation therapy.

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Section: Methodsmentioning

confidence: 99%

Insights into the Mutational Burden of Human Induced Pluripotent Stem Cells from an Integrative Multi-Omics Approach

et al. 2018

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“…There are two major DNase families, DNase I and DNase II, and multiple enzymes in each family play diverse roles in the development of various diseases 16 . Among these nucleases, DNase I has the widest description in DNase I family, 16 and the activity of DNase I has been reported to relate to the occurrence of systemic diseases (like systemic lupus erythematosus), 17‐20 different organ cancers, 21‐23 and inflammatory disease 24,25 . Previous study have confirmed that DNase I‐dependent NETs degradation was an important treatment for diabetic skin wound 15 .…”

Section: Introductionmentioning

confidence: 92%

DNase I improves corneal epithelial and nerve regeneration in diabetic mice

Zhang

Dai

Wei

et al. 2020

J Cellular Molecular Medi

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DNase I has been reported to improve diabetic wound healing through the clearance of neutrophils extracellular traps (NETs) caused by neutrophil aggregation. However, the function of DNase I on diabetic corneal wound healing remains unclear. Here, we investigated the effect and mechanism of topical DNase I application on diabetic mouse corneal epithelial and nerve regeneration. Corneal epithelial defects, inflammatory response, regeneration-related signalling pathways, oxidative stress, corneal innervation and sensation were examined and compared between the diabetic and normal mice. The results confirmed firstly the increased NETs production during the delayed corneal epithelial wound healing of diabetic mice, which was significantly improved through either DNase I or Cl-amidine administration. Mechanistically, DNase I improved inflammation resolution, reactivated epithelial regeneration-related signalling pathways and attenuated the accumulation of reactive oxygen species (ROS).Moreover, DNase I application also promoted corneal nerve regeneration and restored the impaired corneal sensitivity in diabetic mice. Therefore, these results indicate that topical DNase I application promotes corneal epithelial wound healing and mechanical sensation restoration in diabetic mice, representing the potential therapeutic approach for diabetic keratopathy. K E Y W O R D Scorneal wound healing, diabetes mellitus, DNase I, inflammation, oxidative stress

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“…Gene expression profiles from hundreds of patient samples have allowed the identification of several PDA subtypes, with implications for treatment response and patient outcome 5–10 . Gene expression can be dysregulated in cancer through a variety of mechanisms, including genomic amplification/deletion, epigenetic modification and noncoding mutations in promoters/enhancers 11–15 . For example, recurrent noncoding mutations in PDA are enriched in promoters of cancer-associated genes and pathways 16 .…”

Section: Introductionmentioning

confidence: 99%

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Venkat

Tisdale

Schwarz

et al. 2019

Preprint

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Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3’-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDAs). We report widespread, recurrent and functionally relevant 3’-UTR alterations associated with gene expression changes of known and newly identified PDA growth-promoting genes and experimentally validate the effects of these APA events on expression. We find enrichment for APA events in genes associated with known PDA pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3’-UTR forms of metabolic genes. Survival analyses reveal a subset of 3’-UTR alterations that independently characterize a poor prognostic cohort among PDA patients. Finally, we identify and validate the casein kinase CK1α as an APA-regulated therapeutic target in PDA. Knockdown or pharmacological inhibition of CK1α attenuates PDA cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of pro-tumorigenic gene expression in PDA via the loss of miRNA regulation.

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Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer

Cited by 23 publications

References 76 publications

Insights into the Mutational Burden of Human Induced Pluripotent Stem Cells from an Integrative Multi-Omics Approach

Insights into the Mutational Burden of Human Induced Pluripotent Stem Cells from an Integrative Multi-Omics Approach

DNase I improves corneal epithelial and nerve regeneration in diabetic mice

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

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