Goldmine integrates information placing genomic ranges into meaningful biological contexts

Bhasin, Jeffrey M.; Ting, Angela H.

doi:10.1093/nar/gkw477

Cited by 29 publications

(25 citation statements)

References 37 publications

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“…To overcome limitations of previous methods for generating background sequences, we designed GENRE to allow a user to choose genomic features that represent potential biases for the sequence, e.g. GC content, CpG dinucleotide frequency (Bhasin and Ting, 2016; Spruijt and Vermeulen, 2014), the overlaps with repeat sequences (Boeva, 2016) (“repeat overlap”) and with the promoters (“promoter overlap”), defined as the 2 kb regions upstream of transcription start sites (TSS, STAR Methods ).…”

Section: Resultsmentioning

confidence: 99%

Identification of Human Lineage-Specific Transcriptional Coregulators Enabled by a Glossary of Binding Modules and Tunable Genomic Backgrounds

et al. 2017

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Summary Transcription factors (TFs) control cellular processes by binding specific DNA motifs to modulate gene expression. Motif enrichment analysis of regulatory regions can identify direct and indirect TF binding sites. Here, we created a glossary of 108 non-redundant TF-8mer “modules” of shared specificity for 671 metazoan TFs from publicly available and new universal Protein Binding Microarray (PBM) data. Analysis of 239 ENCODE TF ChIP-seq datasets and associated RNA-seq profiles suggest the 8mer modules are more precise than position weight matrices (PWMs) in identifying indirect binding motifs and their associated tethering TFs. We also developed GENRE (Genomically Equivalent Negative REgions), a tunable tool for construction of matched genomic background sequences for analysis of regulatory regions. GENRE outperformed four state-of-the-art approaches to background sequence construction. We used our TF-8mer glossary and GENRE in the analysis of the indirect binding motifs for the co-occurrence of tethering factors, suggesting novel TF-TF interactions. We anticipate that these tools will aid in elucidating tissue-specific gene regulatory programs.

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Section: Resultsmentioning

confidence: 99%

Identification of Human Lineage-Specific Transcriptional Coregulators Enabled by a Glossary of Binding Modules and Tunable Genomic Backgrounds

et al. 2017

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“…Statistical and graphical analyses were conducted using R version 3.3.2 ( R Core Team 2016 ). Genomic feature annotation was performed using the Goldmine R package version 1.0 ( Bhasin and Ting 2016 ). Gene model features were obtained from RefSeq annotations (February 17, 2017) ( O’Leary et al 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Base-Resolution Analysis of DNA Methylation Patterns Downstream of Dnmt3a in Mouse Naïve B Cells

Duncan

Kondilis-Mangum

Grimm

et al. 2018

G3 Genes|Genomes|Genetics

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The DNA methyltransferase, Dnmt3a, is dynamically regulated throughout mammalian B cell development and upon activation by antigenic stimulation. Dnmt3a inactivation in hematopoietic stem cells has been shown to drive B cell-related malignancies, including chronic lymphocytic leukemia, and associates with specific DNA methylation patterns in transformed cells. However, while it is clear that inactivation of Dnmt3a in hematopoietic stem cells has profound functional effects, the consequences of Dnmt3a inactivation in cells of the B lineage are unclear. To assess whether loss of Dnmt3a at the earliest stages of B cell development lead to DNA methylation defects that might impair function, we selectively inactivated Dnmt3a early in mouse B cell development and then utilized whole genome bisulfite sequencing to generate base-resolution profiles of Dnmt3a+/+ and Dnmt3a−/− naïve splenic B cells. Overall, we find that global methylation patterns are largely consistent between Dnmt3a+/+ and Dnmt3a−/− naïve B cells, indicating a minimal functional effect of DNMT3A in mature B cells. However, loss of Dnmt3a induced 449 focal DNA methylation changes, dominated by loss-of-methylation events. Regions found to be hypomethylated in Dnmt3a−/− naïve splenic B cells were enriched in gene bodies of transcripts expressed in B cells, a fraction of which are implicated in B cell-related disease. Overall, the results from this study suggest that factors other than Dnmt3a are the major drivers for methylome maintenance in B cell development.

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“…One sample with low enrichment of methylated DNA was removed from further methylome analysis (Table 1 ). Genomic features and context were resolved using the R package Goldmine 43 using default arguments. The global methylation index was determined as area under the curve using the trapezoidal approximation.…”

Section: Methodsmentioning

confidence: 99%

Interplay between maternal Slc6a4 mutation and prenatal stress: a possible mechanism for autistic behavior development

Sjaarda

Hecht

McNaughton

et al. 2017

Sci Rep

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The low activity allele of the maternal polymorphism, 5HTTLPR, in the serotonin transporter, SLC6A4, coupled with prenatal stress is reported to increase the risk for children to develop autism spectrum disorder (ASD). Similarly, maternal Slc6a4 knock-out and prenatal stress in rodents results in offspring demonstrating ASD-like characteristics. The present study uses an integrative genomics approach to explore mechanistic changes in early brain development in mouse embryos exposed to this maternal gene-environment phenomenon. Restraint stress was applied to pregnant Slc6a4 +/+ and Slc6a4 +/− mice and post-stress embryonic brains were assessed for whole genome level profiling of methylome, transcriptome and miRNA using Next Generation Sequencing. Embryos of stressed Slc6a4 +/+ dams exhibited significantly altered methylation profiles and differential expression of 157 miRNAs and 1009 genes affecting neuron development and cellular adhesion pathways, which may function as a coping mechanism to prenatal stress. In striking contrast, the response of embryos of stressed Slc6a4 +/− dams was found to be attenuated, shown by significantly reduced numbers of differentially expressed genes (458) and miRNA (0) and genome hypermethylation. This attenuated response may pose increased risks on typical brain development resulting in development of ASD-like characteristics in offspring of mothers with deficits in serotonin related pathways during stressful pregnancies.

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Goldmine integrates information placing genomic ranges into meaningful biological contexts

Cited by 29 publications

References 37 publications

Identification of Human Lineage-Specific Transcriptional Coregulators Enabled by a Glossary of Binding Modules and Tunable Genomic Backgrounds

Identification of Human Lineage-Specific Transcriptional Coregulators Enabled by a Glossary of Binding Modules and Tunable Genomic Backgrounds

Base-Resolution Analysis of DNA Methylation Patterns Downstream of Dnmt3a in Mouse Naïve B Cells

Interplay between maternal Slc6a4 mutation and prenatal stress: a possible mechanism for autistic behavior development

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