Understanding the mechanisms driving phenotypic variation is a major goal of biology that unifies classical genetics with the emerging fields of genomics and epigenomics. Human and mouse share over 90% of genes and global tissue-specific patterns of expression are maintained between the species. Thus, it is hypothesized that gene expression is influenced through distinctive regulation among species in order to account for the unmistakable phenotypic divergence. DNA methylation, histone modifications, open chromatin patterns, transcription factor binding, and other epigenetic factors are all associated with shaping, maintaining, and repressing regulatory regions which in turn coordinate gene expression. It is vital to first understand if epigenetic mechanisms are impacting gene expression concordantly across species and second discern how epigenetic regulation is conserved at the tissue level. Furthermore, cell types even within the same tissue diverge in their transcriptomic and epigenomic profiles. Thus, third we must deconvolute tissue-level epigenetics through the study of individual cell types. Here we work towards the goal of a more complete understanding of epigenetic regulation through 1) an epigenome evolution DNA methylation study across blood, brain, and sperm in human, mouse, and rat and 2) assessment of distinct and shared epigenetic profiles of mouse astrocytes, oligodendrocytes, and motor neurons. We find that while tissue-specific regions of hypomethylation are more likely to have orthologous counterparts than expected, less than half maintained tissue-specific hypomethylation within the compared species. For regions that are epigenetically conserved, there is evidence for enrichment of active histone marks and regulatory function along with higher overlap with genetically defined conserved regions. Transcription factor motif maintenance is seen for epigenetically conserved regions and turnover of binding sites could account for tissue-specific hypomethylation that is not epigenetically conserved. We find that epigenetically, glia are more similar to each other than to compared neuronal populations and that motor neurons are distinct from other neurons in their relative lack of hypomethylated regions. Cell type-specific open chromatin patterns and CpG hypomethylated regions track well with increased cell type gene expression. In addition, non-CpG methylation is enriched in neurons, but also seems to retain a putative repressive role in glia. Clustered open chromatin regions function in gene regulation as exemplified through our discovery of putative oligodendrocyte-specific enhancers that overlap a deletion in quakingviable mice; which are known to have oligodendroglial defects and aberrant Qk protein expression. Collectively, these data suggest general paradigms of epigenetics that are shared across species, tissues, and cell types, but only partial maintenance of tissue-specific regulatory regions across species and both shared and cell type-specific epigenetic regulation even within the same tissue
