Abstract
BackgroundThe purpose of this study is to: i) develop a computational model of promoters of human histone-encoding genes (shortly histone genes), an important class of genes that participate in various critical cellular processes, ii) use the model so developed to identify regions across the human genome that have similar structure as promoters of histone genes; such regions could represent potential genomic regulatory regions, e.g. promoters, of genes that may be coregulated with histone genes, and iii/ identify in this way genes that have high likelihood of being coregulated with the histone genes.ResultsWe successfully developed a histone promoter model using a comprehensive collection of histone genes. Based on leave-one-out cross-validation test, the model produced good prediction accuracy (94.1% sensitivity, 92.6% specificity, and 92.8% positive predictive value). We used this model to predict across the genome a number of genes that shared similar promoter structures with the histone gene promoters. We thus hypothesize that these predicted genes could be coregulated with histone genes. This hypothesis matches well with the available gene expression, gene ontology, and pathways data. Jointly with promoters of the above-mentioned genes, we found a large number of intergenic regions with similar structure as histone promoters.ConclusionsThis study represents one of the most comprehensive computational analyses conducted thus far on a genome-wide scale of promoters of human histone genes. Our analysis suggests a number of other human genes that share a high similarity of promoter structure with the histone genes and thus are highly likely to be coregulated, and consequently coexpressed, with the histone genes. We also found that there are a large number of intergenic regions across the genome with their structures similar to promoters of histone genes. These regions may be promoters of yet unidentified genes, or may represent remote control regions that participate in regulation of histone and histone-coregulated gene transcription initiation. While these hypotheses still remain to be verified, we believe that these form a useful resource for researchers to further explore regulation of human histone genes and human genome. It is worthwhile to note that the regulatory regions of the human genome remain largely un-annotated even today and this study is an attempt to supplement our understanding of histone regulatory regions.
Highlights
The purpose of this study is to: i) develop a computational model of promoters of human histoneencoding genes, an important class of genes that participate in various critical cellular processes, ii) use the model so developed to identify regions across the human genome that have similar structure as promoters of histone genes; such regions could represent potential genomic regulatory regions, e.g. promoters, of genes that may be coregulated with histone genes, and iii/ identify in this way genes that have high likelihood of being coregulated with the histone genes
We used the standalone version of Dragon Promoter Mapper (DPM) tool [2] to develop a Bayesian network (BN) based histone promoter model by exploiting several features that may reflect the biology associated with these promoters
Analysis of Biological terms For genes that we identified as having similar promoter structure as histone promoters, we tested for enriched Gene Ontology (GO) annotation and protein interaction networks with GOEAST [29] and Ingenuity Pathway Analysis (IPA) system
Summary
The purpose of this study is to: i) develop a computational model of promoters of human histoneencoding genes (shortly histone genes), an important class of genes that participate in various critical cellular processes, ii) use the model so developed to identify regions across the human genome that have similar structure as promoters of histone genes; such regions could represent potential genomic regulatory regions, e.g. promoters, of genes that may be coregulated with histone genes, and iii/ identify in this way genes that have high likelihood of being coregulated with the histone genes. Our assumption is that two genes with sufficiently similar promoter structures have an increased chance to be coregulated and coexpressed This stems from the understanding that one of the key point of gene regulation happens at the transcription stage where the promoters play the most crucial role. To determine these potential regulatory regions, we developed a statistical model to capture regulatory signals in the promoters of human histone genes, which we used to analyze the human genome. These results matched well with the known experimental data and we found them to be statistically significant
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