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H-DNA as a Potential cis-Element Regulating Gene Expression
Subhankar Chakraborty

DNA triplexes are formed when a polypurine segment of duplex DNA is recognized and bound by a single stranded oligonucleotide lodging in the major groove of the duplex. Such a single stranded oligonucleotide is termed as a triplex-forming oligonucleotide (TFO) while the sequence with which it interacts is called the triplex-targeting sequence (TTS). The TFO can be either DNA, RNA or any oligonucleotide with modifications in its nucleobases or the phosphoribose backbone. Based on the orientation of the TFO with respect to the central polypurine tract, two types of orientation can be discerned: i) parallel form characterized by formation of Hoogsteen bonds between the TFO which is typically pyrimidine rich, and the polypurine strand of the duplex, and ii) antiparallel form wherein the TFO is polypurine rich and forms reverse-Hoogsteen bonds with the polypurine strand.

An analysis of the human genome showed that TTS regions (sequences that are expected to form stable triplexes under physiological conditions)are vastly over-represented in the genome, far more than can be expected to occur purely by chance. Significantly, the greatest number of these sequences occur just upstream of regulatory regions (mostly within 100 nucleotides 5' of the promoter region ) of genes. Moreover, genes with a TTS upstream of their promoters have important physiological functions, often coding for transcription factors or related proteins. However, mapping of the promoter region upto 200 bases upstream of the transcription start site in those genes which contained potential triplex DNA forming sequences did not reveal any consensus sequence for binding of transcription factors. Another possibility was that the TTS located in the promoter region of a gene was involved in triplex formation with a complimentary sequence in the intron region of another gene thereby achieving negative regulation of gene expression. However, a search failed to reveal any relationship between genes with a TTS in their intron region with a complimentary TFO in the intron of another gene. But the gross over-abundance of TTS sequences is too obvious to ignore as being non-functional. Investigation into the physical differences between TTS and duplex forming DNA regions led to the observation that triplex forming segments of the DNA are significantly more curved and rigid than their duplex forming counterparts. While

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