Abstract
BackgroundStudies have shown the strong association between histone modification levels and gene expression levels. The detailed relationships between the two can vary substantially due to differential regulation, and hence a simple regression model may not be adequate. We apply a regression hidden Markov model (regHMM) to further investigate the potential multiple relationships between genes and histone methylation levels in mouse embryonic stem cells.ResultsSeven histone methylation levels are used in the study. Averaged histone modifications over non-overlapping 200 bp windows on the range transcription starting site (TSS) ± 1 Kb are used as predictors, and in total 70 explanatory variables are generated. Based on regHMM results, genes segregated into two groups, referred to as State 1 and State 2, have distinct association strengths. Genes in State 1 are better explained by histone methylation levels with R2=.72 while those in State 2 have weaker association strength with R2=.38. The regression coefficients in the two states are not very different in magnitude except in the intercept,.25 and 1.15 for State 1 and State 2, respectively. We found specific GO categories that may be attributed to the different relationships. The GO categories more frequently observed in State 2 match those of housekeeping genes, such as cytoplasm, nucleus, and protein binding. In addition, the housekeeping gene expression levels are significantly less explained by histone methylation in mouse embryonic stem cells, which is consistent with the constitutive expression patterns that would be expected.ConclusionGene expression levels are not universally affected by histone methylation levels, and the relationships between the two differ by the gene functions. The expression levels of the genes that perform the most common housekeeping genes’ GO categories are less strongly associated with histone methylation levels. We suspect that additional biological factors may also be strongly associated with the gene expression levels in State 2. We discover that the effect of the presence of CpG island in TSS ± 1 Kb is larger in State 2.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-360) contains supplementary material, which is available to authorized users.
Highlights
Studies have shown the strong association between histone modification levels and gene expression levels
To better understand the biological mechanism in gene regulation, we investigated the potential multiple relationships between gene expression levels and histone methylation levels around transcription starting site (TSS) ± 1 Kb in mouse embryonic stem cells
The genes are categorized into two groups, and the gene expression levels are better explained by histone methylation levels in one group (State 1) than in another (State 2)
Summary
Studies have shown the strong association between histone modification levels and gene expression levels. We apply a regression hidden Markov model (regHMM) to further investigate the potential multiple relationships between genes and histone methylation levels in mouse embryonic stem cells. Histone modifications are known as a major gene regulatory factor along with transcription factors [1,2]. Studies suggest that chemically modified histones, such as methylated or acetylated, contribute to gene regulation by altering the DNA accessibility of transcription factors. When the transcription factors bind to a DNA promoter or enhancer region, they activate or enhance gene transcription, respectively [3]. There have been many studies for detecting the association between histone modifications and gene expression levels. H3K4 monomethylation (H3K4me1) is associated with gene enhancer activity.
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