With the advent of next-generation sequencing technologies, a considerable effort has been put into sequencing the epigenome of different species. The efforts such as “Encode” and “Roadmap” epigenomics projects provide an opportunity to compare epigenomes across species (especially between human and mouse). This study is an effort to understand how different histone modifications vary/co-appear between orthologus regions of the two species. In this work, we have also used various measures of orthologus similarity between each pair of orthologus genes and explore how histone modifications are conserved with respect to changes in these similarity measures. These measures of similarity include “gene ontology semantic similarity” (GOSemsim), “codon usage frequency similarity” (CUFS), Ka/Ks ratio and gene expression similarity. Our simulations indicate that evolutionary selection pressure of an orthologus pair (Ka/Ks ratio) is more strongly correlated with its histone modification than any other similarity measure.