Differential contribution to gene expression prediction of histone modifications at enhancers or promoters

Whereas the ChIP-seq signal of histone modifications at promoters is reported to be a good predictor of gene expression in different cellular contexts, this question has been poorly addressed for enhancers. Embryonic stem cells (ESCs) ―where the full spectrum of active and repressed (poised) enhancers can be identified― are the appropriate model system to tackle this problem. Since many poised enhancers in ESCs switch towards an active state during differentiation, predictive models can be learnt from poised enhancers throughout differentiation. Modelling gene expression from histone modifications at enhancers will allow us to study the different contribution of promoters and enhancers to gene expression. We have obtained quantitative models to characterize the relationship of gene expression with histone modifications at enhancers or promoters. Remarkably, we have determined that histone modifications at enhancers, as well as promoters, are predictive of gene expression in ESCs and throughout differentiation. The contribution of histone modifications to the predictive models varies depending on their location in enhancers or promoters. We have designed a novel approach based on local regression (LOESS) to normalize sequencing data from different sources, which allowed us to apply predictive models learnt in a specific cellular context to a different one. Therefore, this allowed us to conclude that the relationship between gene expression and histone modifications at enhancers is universal. ChIP-seq experiments of mESC