Akhtar, Most. Maluluda (2013) Epigenetic modifications in CpG islands and signatures of selective pressure in human genome. [Tesi di dottorato]

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Epigenetics deals the heritable changes in gene regulation which is not related with the changes of DNA sequence itself. Among several molecular mechanisms that mediate epigenetic phenomena, DNA methylation and histone modifications are well known markers. CpG islands (CGIs) are the key epigenomic elements in mammalian genome. CGIs are defined as the segments of the genome that show increased level of CpG dinucleotides and GC content. These CGIs are enriched at genes, about 60% of all genes in the human genome containing a CGI upstream. DNA methylation at CGIs is one of the most intensively studied epigenetic mechanisms. It is fundamental for cellular differentiation and control of transcriptional potential. DNA methylation is involved also in several processes that are central to evolutionary biology, including phenotypic plasticity and evolvability. Furthermore, histone modifications in CGIs are associated with the changes in chromatin states and with transcription activity. Changes in gene expression play a crucial role in adaptation and evolution. Considering the role of DNA methylation and histone modifications in gene expression changes, our aim was to explore the relationship between these two epigenetic marks and selective pressure in human genome. In the first step, we explored a relationship between CpG islands methylation and signatures of selective pressure in Homo sapiens, using a computational biology approach. For this we analyzed methylation data of 25 human cell lines from the Encyclopedia of DNA Elements (ENCODE) Consortium. To define regions under selective pressure, we used three distinct signatures that mark selective events from different evolutionary periods. We compared the DNA methylation of CpG islands in genomic regions under selective pressure with the methylation of CpG islands in the remaining part of the genome. We found that CpG islands in the regions under selective pressure are undermethylated than the CpG islands of the other group. In the second step, we have studied, using a computational biology approach, the relationship between histone modifications in CGIs and selective pressure in Homo sapiens. We considered three histone modifications: histone H3 lysine 4 trimethylation (H3K4me3), acetylation of histone H3 at lysine 27 (H3K27ac) and trimethylation of histone H3 at lysine 36 (H3K36me3), and we used the publicly available genomic-scale histone modification data of 23 human cell lines. To define regions under selective pressure, we used the similar approach as used in the first step. We found that, CGIs under selective pressure showed significant enrichments for histone modifications. In conclusion, our overall findings suggest that CpG islands that experienced selective pressure are characterized by distinct epigenetic signatures.

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