Abstract
The transcriptome of every cell is orchestrated by the complex network of interaction between transcription factors (TFs) and their binding sites on DNA. Disruption of this network can result in many forms of organism malfunction but also can be the substrate of positive natural selection. However, understanding the specific determinants of each of these individual TF-DNA interactions is a challenging task as it requires integrating the multiple possible mechanisms by which a given TF ends up interacting with a specific genomic region. These mechanisms include DNA motif preferences, which can be determined by nucleotide sequence but also by DNA’s shape; post-translational modifications of the TF, such as phosphorylation; and dimerization partners and co-factors, which can mediate multiple forms of direct or indirect cooperative binding. Binding can also be affected by epigenetic modifications of putative target regions, including DNA methylation and nucleosome occupancy. In this review, we describe how all these mechanisms have a role and crosstalk in one specific family of TFs, the basic helix-loop-helix (bHLH), with a very conserved DNA binding domain and a similar DNA preferred motif, the E-box. Here, we compile and discuss a rich catalog of strategies used by bHLH to acquire TF-specific genome-wide landscapes of binding sites.
Highlights
Gene expression is primarily regulated by transcription factors binding and acting on regions of the DNA which, precisely because they host this activity, become what is known as cis-regulatory elements
Early leverage of ChIP-seq data from multiple transcription factors (TFs) and genome-wide chromatin maps revealed that the vast majority of transcription factor binding sites (TFBS) fell on accessible chromatin [2], with the exception of those binding sites associated with chromatin repressors or pioneer TFs
We focused on variability and complexity between members of one particular family of TFs, the basic helix-loop-helix to describe how this multimodal diversity determining the modes of action of TFs and their DNA binding specificities can be found within one structural family of TFs with a highly conserved DNA binding domains (DBD)
Summary
Gene expression is primarily regulated by transcription factors binding and acting on regions of the DNA which, precisely because they host this activity, become what is known as cis-regulatory elements. A recent manually curated census of transcription factors in the human genome identified 1639 of these molecules, classified in around 100 types based on their DNA binding domains (DBD) [1] Those DBD largely, but not completely, determine the DNA sequence preferentially bound by each TF and with that the ability to influence expression on effectively close target genes. Counting canonical motifs matches or binding events, determined in silico and experimentally, respectively, has allowed calculating enrichments of TFBS on specific groups of sequences These methods often provide meaningful global observations on broad dynamics of the regulatory landscape in development, tissue-specific functions, evolution and disease. Similar evidence for purifying selection can be observed when leveraging polymorphism data with fixed substitutions between species on TFBS using a MacDonald–Kreitman framework [8], which, in addition, has the potential to reveal the fraction of adaptive substitutions, i.e., driven by positive selection, in groups of binding sites
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