The recent availability of the complete genome sequences of humans and other species allows comparative genomics approaches, such as phylogenetic footprinting, in order to detect transcription factor-binding sites that are under evolutionary constraint. However, only in combination with experimental data, for example, obtained by the ENCODE consortium, such in silico approaches are effective. The rapidly increasing amount of ChIP-seq data on transcription factor locations and multiple histone modifications significantly changes our understanding of gene regulation. The integration of these new sources of information has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome.
Many transcription factors are far more flexible in the way of recognizing their genomic target sequences than initially assumed. They often recognize a larger number of interacting nuclear proteins and may not always directly contact DNA. This new insight has also consequences on the question, which transcription factor is assigned to the regulation of which gene, i.e. not always the approach applies that sites in rather close vicinity to TSS regions are the main regions for regulation.
In this chapter, we are discussing a number of different approaches for a genome-wide identification of transcription factor-binding sites ranging from in silico comparative genomics over integrating large ChIP-seq data set to assays for a three-dimensional analysis of chromatin looping. Insight obtained from these novel methods provides helps to develop a new model of gene regulation.
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