Computational prediction of CRISPR-impaired non-coding regulatory regions

Baumgarten, Nina; Schmidt, Florian; Wegner, Martin; Hebel, Marie; Schulz, Marcel H.

doi:10.1515/hsz-2020-0392

Cited by 2 publications

(1 citation statement)

References 78 publications

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“…In a cooperation with the lab of Manuel Kaulich, we analyzed CRISPR-induced mutations in the non-coding genome and developed an analysis protocol to identify target genes and to perform functional analyses based on the identified REMs. The work is published as part of the issue Bioinformatics in theory and application of Biological Chemistry with the title Computational prediction of CRISPR-impaired non-coding regulatory regions (Baumgarten et al, 2021). Parts of the text and figures are taken from the publication or similar to it.…”

Section: Application: Computational Prediction Of Crisprimpaired Non-...mentioning

confidence: 99%

Prediction of transcription factor binding using epigenomics and genome variation data

Baumgarten

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A central concern in genetics is to identify mechanisms of transcriptional regulation. The aim is to unravel the mapping between the DNA sequence and gene expression. However, it turned out that this is extremely complex. Gene regulation is highly cell type-specific and even moderate changes in gene ex- pression can have functional consequences. Important contributors to gene regulation are transcription factors (TFs), that are able to directly interact with the DNA. Often, a first step in understanding the effect of a TF on the gene’s regulation is to identify the genomic regions a TF binds to. Therefore, one needs to be aware of the TF’s binding preferences, which are commonly summarized in TF binding motifs. Although for many TFs the binding motif is experimentally validated, there is still a large number of TFs where no binding motif is known. There exist many tools that link TF binding motifs to TFs. We developed the method Massif that improves the performance of such tools by incorporating a domain score that uses the DNA binding domain of the studied TF as additional information. TF binding sites are often enriched in regulatory elements (REMs) such as promoters or enhancers, where the latter can be located megabases away from its target gene. However, to understand the regulation of a gene it is crucial to know where the REMs of a gene are located. We introduced the EpiRegio webserver that holds REMs associated to target genes predicted across many cell types and tissues using STITCHIT, a previously established method. Our publicly available webserver enables to query for REMs associated to genes (gene query) and REMs overlapping genomic regions (region query). We illus- trated the usefulness of EpiRegio by pointing to a TF that occurs enriched in the REMs of differential expressed genes in circPLOD2 depleted pericytes. Further, we highlighted genes, which are affected by CRISPR-Cas induced mutations in non-coding genomic regions using EpiRegio’s region query. Non-coding genetic variants within REMs may alter gene expression by modifying TF binding sites, which can lead to various kinds of traits or diseases. To understand the underlying molecular mechanisms, one aims to evaluate the effect of such genetic variations on TF binding sites. We developed an accurate and fast statistical approach, that can assess whether a single nucleotide polymorphism (SNP) is regulatory. Further, we combined this approach with epigenetic data and additional analyses in our Sneep workflow. For instance, it enables to identify TFs whose binding preferences are affected by the analyzed SNPs, which is illustrated on eQTL datasets for different cell types. Additionally, we used our Sneep workflow to highlight cardiovascular disease genes using regulatory SNPs and REM-gene interactions. Overall, the described results allow a better understanding of REM-gene interactions and their interplay with TFs on gene regulation.

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Section: Application: Computational Prediction Of Crisprimpaired Non-...mentioning

confidence: 99%

Prediction of transcription factor binding using epigenomics and genome variation data

Baumgarten

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Bioinformatics in theory and application – highlights of the 36th German Conference on Bioinformatics

Koch

Andrade‐Navarro

Schulz

et al. 2021

Biological Chemistry

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Computational prediction of CRISPR-impaired non-coding regulatory regions

Cited by 2 publications

References 78 publications

Prediction of transcription factor binding using epigenomics and genome variation data

Prediction of transcription factor binding using epigenomics and genome variation data

Bioinformatics in theory and application – highlights of the 36th German Conference on Bioinformatics

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