ISWI ATPase Snf2h Is Required for Both Heterochromatin and Euchromatin Structure in ES Cells.

Snf2h is a chromatin remodeling ATPase which along with associated factors has the ability to assemble and slide nucleosomes. Snf2h levels are substantially increased in acute leukemia cells and in aggressive solid tumors, suggesting a role for Snf2h in regulating chromatin structure in malignancy. Snf2h-null mice exhibit early embryonic lethality and Snf2h heterozygous mutant mice are growth-retarded (Stopka 2003, Chong 2007). In this study we have used Snf2h hemizygous (+/−) embryonic stem (ES) cells and mice to examine the consequences of reduced Snf2h stoichiometry on chromatin structure. Using indirect immunofluorescence and confocal microscopy we found that Snf2h in ES cells is localized both in euchromatin and to a lesser extent in heterochromatin. Its expression is markedly reduced in Sn2h +/− cells. Chromatin of Snf2h +/− ES cells exhibited multiple defects including decreased amounts of heterochromatin and a significant decrease of euchromatic marks including histone H3K79 and H4K16 acetylation. In contrast, histone H3K9 acetylation and the level of another chromatin remodeling ATPase, Brg-1, was not altered in Snf2h +/− ES cells as compared to wild-type ES cells. Thus in ES cells Snf2h may be involved in formation of both heterochromatin as well as transcriptionaly active euchromatin. Our data support the role of Snf2h in regulation of chromatin structure in leukemia, currently tested using Snf2h heterozygous animals.