Computational identification of promoters and first exons in the human genome.

The identification of promoters and first exons has been one of the most difficult problems in gene-finding. We present a set of discriminant functions that can recognize structural and compositional features such as CpG islands, promoter regions and first splice-donor sites. We explain the implementation of the discriminant functions into a decision tree that constitutes a new program called FirstEF. By using different models to predict CpG-related and non-CpG-related first exons, we showed by cross-validation that the program could predict 86% of the first exons with 17% false positives. We also demonstrated the prediction accuracy of FirstEF at the genome level by applying it to the finished sequences of human chromosomes 21 and 22 as well as by comparing the predictions with the locations of the experimentally verified first exons. Finally, we present the analysis of the predicted first exons for all of the 24 chromosomes of the human genome.     

Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome

To gain insight into the function of DNA methylation at cis-regulatory regions and its impact on gene expression, we measured methylation, RNA polymerase occupancy and histone modifications at 16,000 promoters in primary human somatic and germline cells. We find CpG-poor promoters hypermethylated in somatic cells, which does not preclude their activity. This methylation is present in male gametes and results in evolutionary loss of CpG dinucleotides, as measured by divergence between humans and primates. In contrast, strong CpG island promoters are mostly unmethylated, even when inactive. Weak CpG island promoters are distinct, as they are preferential targets for de novo methylation in somatic cells. Notably, most germline-specific genes are methylated in somatic cells, suggesting additional functional selection. These results show that promoter sequence and gene function are major predictors of promoter methylation states. Moreover, we observe that inactive unmethylated CpG island promoters show elevated levels of dimethylation of Lys4 of histone H3, suggesting that this chromatin mark may protect DNA from methylation.