LSH catalyzes ATP-driven exchange of histone variants macroH2A1 and macroH2A2

LSH, a homologue of the ISWI/SNF2 family of chromatin remodelers, is required in vivo for deposition of the histone variants macroH2A1 and macroH2A2 at specific genomic locations. However, it remains unknown whether LSH is directly involved in this process or promotes other factors. Here we show that recombinant LSH interacts in vitro with macroH2A1–H2B and macroH2A2–H2B dimers, but not with H2A.Z–H2B dimers. Moreover, LSH catalyzes the transfer of macroH2A into mono-nucleosomes reconstituted with canonical core histones in an ATP dependent manner. LSH requires the ATP binding site and the replacement process is unidirectional leading to heterotypic and homotypic nucleosomes. Both variants macroH2A1 and macroH2A2 are equally well incorporated into the nucleosome. The histone exchange reaction is specific for histone variant macroH2A, since LSH is not capable to incorporate H2A.Z. These findings define a previously unknown role for LSH in chromatin remodeling and identify a novel molecular mechanism for deposition of the histone variant macroH2A.