Enhanced C/EBPs binding to C&gt;T mismatches facilitates fixation of CpG mutations

Ershova, Anna S.; Eliseeva, Irina A.; Nikonov, Oleg; Fedorova, Alla D.; Vorontsov, Ilya E.; Papatsenko, Dmitry; Kulakovskiy, Ivan V.

doi:10.1101/2020.06.11.146175

Cited by 3 publications

(2 citation statements)

References 44 publications

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“…These cytosines belong to the core CG pair which is prone to spontaneous deamination. The produced mismatches are then protected from repair through enhanced CEBPB binding resulting in mutation fixation 34 . Such ASBs, on the one hand, confirm frequent mutagenesis of CEBPB binding sites, and, on the other hand, suggest the action of purifying selection that stabilizes such sites as heterozygous variants.…”

Section: Resultsmentioning

confidence: 99%

Landscape of allele-specific transcription factor binding in the human genome

Abramov

Boytsov

Bykova

et al. 2020

Preprint

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Sequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with pathologies and often act as eQTLs, revealing molecular mechanisms and causality of the associations. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus providing allele-specific molecular machinery for the target gene regulation.

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Section: Resultsmentioning

confidence: 99%

Landscape of allele-specific transcription factor binding in the human genome

Abramov

Boytsov

Bykova

et al. 2020

Preprint

Self Cite

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“…Notably, they found that 5-methylcytosine at the CG site enhances binding of CEBPB. Enhanced binding of CEBPB with C>T mutations at base 5 of the motif was recently confirmed by Ershova et al (2020) Preprint .…”

Section: Resultsmentioning

confidence: 82%

Functional annotation of noncoding mutations in cancer

et al. 2021

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In a cancer genome, the noncoding sequence contains the vast majority of somatic mutations. While very few are expected to be cancer drivers, those affecting regulatory elements have the potential to have downstream effects on gene regulation that may contribute to cancer progression. To prioritize regulatory mutations, we screened somatic mutations in the Pan-Cancer Analysis of Whole Genomes cohort of 2,515 cancer genomes on individual bases to assess their potential regulatory roles in their respective cancer types. We found a highly significant enrichment of regulatory mutations associated with the deamination signature overlapping a CpG site in the CCAAT/Enhancer Binding Protein β recognition sites in many cancer types. Overall, 5,749 mutated regulatory elements were identified in 1,844 tumor samples from 39 cohorts containing 11,962 candidate regulatory mutations. Our analysis indicated 20 or more regulatory mutations in 5.5% of the samples, and an overall average of six per tumor. Several recurrent elements were identified, and major cancer-related pathways were significantly enriched for genes nearby the mutated regulatory elements. Our results provide a detailed view of the role of regulatory elements in cancer genomes.

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Landscape of allele-specific transcription factor binding in the human genome

et al. 2021

View full text Add to dashboard Cite

Sequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with phenotypes of medical relevance and often overlap eQTLs, making candidates for causality by linking variants with molecular mechanisms. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus revealing allele-specific rewiring of molecular circuitry.

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Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

Cited by 3 publications

References 44 publications

Landscape of allele-specific transcription factor binding in the human genome

Landscape of allele-specific transcription factor binding in the human genome

Functional annotation of noncoding mutations in cancer

Landscape of allele-specific transcription factor binding in the human genome

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