Epigenetic mechanisms are crucial for chromatin structure reprogramming and gene expression during mammalian development and cell differentiation. Dysregulation of epigenetic information is implicated in many human diseases including cancer because it disrupts fundamental processes such as imprinting, X chromosome inactivation, and tissue specific and developmental gene regulation. H1 linker histones are major chromatin structural proteins that associate with nucleosome core particles and play a key role in mediating higher order chromatin structure folding. Previously we showed, by inactivating 3 H1 linker histone genes simultaneously, that the total amount of H1 is essential for mammalian development. We derived triple H1 null embryonic stem cell lines and showed that H1 is particularly important in controlling several imprinted gene expression in these cells. These studies suggested a new link between H1 and DNA methylation. Using genetic modified mouse models and stem cell culture system, we seek to further elucidate the mechanisms of the multiple levels of epigenetic regulations that are required for establishing and maintaining tissue and cell type specific functions.