Abstract
i-Motifs are widely used in nanotechnology, play a part in gene regulation and have been detected in human nuclei. As these structures are composed of cytosine, they are potential sites for epigenetic modification. In addition to 5-methyl- and 5-hydroxymethylcytosine modifications, recent evidence has suggested biological roles for 5-formylcytosine and 5-carboxylcytosine. Herein the human telomeric i-motif sequence was used to examine how these four epigenetic modifications alter the thermal and pH stability of i-motifs. Changes in melting temperature and transitional pH depended on both the type of modification and its position within the i-motif forming sequence. The cytosines most sensitive to modification were next to the first and third loops within the structure. Using previously described i-motif forming sequences, we screened the MCF-7 and MCF-10A methylomes to map 5-methylcytosine and found the majority of sequences were differentially methylated in MCF7 (cancerous) and MCF10A (non-cancerous) cell lines. Furthermore, i-motif forming sequences stable at neutral pH were significantly more likely to be epigenetically modified than traditional acidic i-motif forming sequences. This work has implications not only in the epigenetic regulation of DNA, but also allows discreet tunability of i-motif stability for nanotechnological applications.
Highlights
The information available from DNA is multi-layered
There is a correlation between methylation of CpG islands near transcription start sites and gene silencing [5], these are important in epigenetic control of gene expression
Given the unexplored additional potential epigenetic modifications, 5fC and 5caC and the untested cytosine positions in the human telomeric sequence, we describe a systematic study to examine how these modifications alter i-motif stability and where they have the most impact on the stability of i-motif structure
Summary
The information available from DNA is multi-layered. Its raw sequence can code for proteins and regulatory elements [1], and emerging evidence has shown that secondary DNA structures can influence how and when genes are expressed [2,3]. The effect of epigenetic modification on the stability of i-motif DNA structures has been investigated using specific examples. Previous work has examined the effect on i-motif stability with the modification of an individual cytosine in a single position to a methyl- or hydroxymethylcytosine [18,21].
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