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Genome-wide approaches like high-throughput DNA- and RNA-sequencing have shown that only a small part of eukaryotic genomes codes for proteins (e.g. in human only 1.5%). However, virtually the whole non-coding part is also transcribed, giving rise to thousands of non-coding RNAs (ncRNAs). The biological role of these ncRNAs has been intensively investigated over last decade, showing that they have various functions in the cell nucleus and the cytoplasm. One of the most interesting features of ncRNAs is that many of them can modulate the chromatin state in a site-specific manner. However, in most cases it is not clear how ncRNAs find their specific target sites in the genome.

Tethering via chromatin-bound proteins can be one mechanism, but is indirect and has limited discriminative power. Therefore, direct sequence-specific interactions of ncRNAs with genomic DNA are better suited. This is the case for the building of triple stranded RNA/DNA structures like triple helices (triplexes), in which the RNA binds to the major groove of the DNA double helix via Hoogsteen base pairing.

RNA:DNA triplexes have certain sequence requirements and thus allow a relaxed sequence specificity between both nucleic acids, i.e. triplex-forming RNAs can act in cis or in trans at one or several genomic loci. These features, together with the non-invasive interaction with DNA, make RNA:DNA triplex formation a very attractive targeting mechanism for ncRNAs. However, the detection of RNA:DNA triplexes in cells is very difficult and there are only a few reports describing a role of these structures in gene regulation.