Mcm2 promotes stem cell differentiation via its ability to bind H3-H4

Mcm2, a subunit of the Mcm2-7 helicase best known for its role in DNA replication, contains a histone binding motif that facilitates the transfer of parental histones following DNA replication. Here we show that Mcm2 is important for the differentiation of mouse embryonic stem (ES) cells. The Mcm2-2A mutation defective in histone binding impairs differentiation and disrupts the programmatic changes in gene expression and histone modifications during differentiation. Mcm2 localizes at transcription starting sites and the binding of Mcm2 at gene promoters is disrupted in both Mcm2-2A ES cells and neuro-precursor cells (NPCs). Reduced Mcm2 binding at bivalent chromatin domains containing repressive H3K27me3 and active H3K4me3 modifications in Mcm2-2A ES cells correlates with decreased chromatin accessibility at corresponding sites in NPCs. Together, our studies reveal a novel function of Mcm2 in ES cell differentiation, likely through manipulating chromatin landscapes at bivalent chromatin domains.