## 1 Introduction  
The gene is the fundamental unit on the genomic DNA which contains the required information to carry out the biological functions of cells. The expression of genes i.e. mRNA synthesis can be measured efficiently in a high-throughput fashion and such expression patterns are characteristic of cellular responses to external stimuli [1]. It is widely accepted that these responses are mainly driven by the interactions between transcription factors (TFs) and their corresponding transcription factor binding sites (TFBSs) on the proximal promoters of the target genes [2, 3]. However, with a large number of genes in eukaryotic genomes, deciphering how these interactions evolve to control the expression of tens of thousands of genes (\(\sim\) 35,000 genes in human) remains an open question. Recent studies [4] have shown that the underlying regulatory mechanisms are complex, dynamic (especially in higher organisms) and can be arranged in multiple hierarchical levels such as the sequence, the chromatin, and the nuclear level. The sequence level, also the best-studied level of gene regulation, is characterized by the linear organization of transcription units and _cis_-regulatory elements considered as the regulatory code which governs gene expression. These _cis_-regulatory elements i.e. binding sites which are more important when found on the proximal promoters form a highly flexible and context-dependent structure [5] for each gene [6-8]. Furthermore, in eukaryotic cells genomic DNA is 'packed' into an efficient structure, called chromatin, composed of nucleosomes that consist of approximately 147 bp of DNA wrapped around a protein octamer [9, 10]. This structure not only packs DNA but also creates an added layer of gene regulation which ensures correct gene expression and accessibility to DNA-dependent processes e.g. gene transcription, DNA repair, and DNA replication. The overall process of the transcription process encompassing the nuclear architecture and/or the complex spatial arrangement of genes, gene clusters, chromatin, and regulatory DNA elements [11, 12] is far beyond the scope of any single review and hence we only focus on the sequence level aiming at discovering _cis_-regulatory elements on the proximal promoters. Two of the most important functional elements in gene regulation are transcription factors and their binding sites on the promoters of their target genes. A TF is a protein which binds to specific DNA binding motifs that can be present multiple times on the same promoter of a gene or on different promoters of different genes. The transcription factor binding sites where a TF binds are usually short (5 - 15 bp) and degenerate but highly selective through evolution [13]. A gene can have multiple alternative promoters [14, 15] and each promoter frequently contains a large number of binding sites (10 - 50 binding sites) for 5 - 15 different TFs [16]. Therefore, a more comprehensive understanding of these elements and their interactions will provide a deeper understanding of the regulatory pathways within cells and potential functions of individual genes and/or gene clusters [17]. Although various approaches have been developed, we are still limited by both experimental and computational techniques in order to detect these binding sites and understand their interplay with corresponding TFs as well as their role in the transcription process. However, recent high-throughput technologies which identify high-affinity binding sequences e.g. ChIP-chip [18, 19], SELEX [20, 21] revealed the genomic regions to which a particular TF is bound, providing a powerful resource for discovering binding sites of transcription factors. Even though the information collected through suchmethods is substantial, how to best annotate and interpret such a large volume of data and how the data can be explored to predict novel binding sites are still open issues.