Technologies for profiling the impact of genomic variants on transcription factor binding.

Janna Leiz,Maria Rutkiewicz,Kai M Schmidt-Ott,Udo Heinemann,Carmen Birchmeier

doi:10.1515/medgen-2021-2073

Abstract

Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby regulate target gene expression. TF binding and its regulatory activity is highly context dependent, and is not only determined by specific cell types or differentiation stages but also relies on other regulatory mechanisms, such as DNA and chromatin modifications. Interactions between TFs and their DNA binding sites are critical mediators of phenotypic variation and play important roles in the onset of disease. A continuously growing number of studies therefore attempts to elucidate TF:DNA interactions to gain knowledge about regulatory mechanisms and disease-causing variants. Here we summarize how TF-binding characteristics and the impact of variants can be investigated, how bioinformatic tools can be used to analyze and predict TF:DNA binding, and what additional information can be obtained from the TF protein structure.

Highlights

Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby regulate target gene expression
We summarize how TF-binding characteristics and the impact of variants can be investigated, how bioinformatic tools can be used to analyze and predict TF:DNA binding, and what additional information can be obtained from the TF protein structure
It is often challenging to identify disease-associated variants and to prove causation, several studies show that variants in the regulatory genome alter TF:DNA interactions and are associated with altered target gene expression and disease [9, 10]

Summary

Introduction

Abstract: Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby regulate target gene expression. It is often challenging to identify disease-associated variants and to prove causation, several studies show that variants in the regulatory genome alter TF:DNA interactions and are associated with altered target gene expression and disease [9, 10] This emphasizes the necessity of examining genetic variants in the context of patient clinical phenotypes. All three binding sites are in close proximity, and disruption of either one of them significantly decreases promoter activity, indicating a possible cooperation of HNF4α, ONECUT1/2, and C/EBPα to control F9 expression This example shows how alterations of single bases in TF-binding motifs can disrupt TF:DNA interactions and critically alter gene expression leading to disease [11]. Technologies for profiling the impact of genomic variants on transcription factor binding | 149

How can transcription factors and their binding motifs be investigated?

Findings

Future challenges