No abstract

e One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight into the poorly recognized function of macroH2A in transcriptional activation and demonstrate its relevance in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells.

No abstract

The influence of metal cations (M = Cu+, Ca2+ and Cu2+) coordinated to N7 of guanine on the intermolecular proton-transfer reaction in guanine−cytosine base pair has been analyzed using the B3LYP density functional approach. Gas phase metal cation interaction stabilizes the ion pair structure derived from the N1−N3 single-proton-transfer reaction, the effects being more pronounced for the divalent cations than for the monovalent one. For Cu2+GC the reaction is largely favored due to both electrostatic and oxidative effects. Hydration of the metal cation disfavors the reaction due to the screening of electrostatic effects. However, for Cu2+ the reaction can still be easily produced, especially for certain local environments of the metal cation for which Cu2+ induces the oxidation of guanine. Therefore, the ability of Cu2+ to oxidize guanine turns out to be a key factor for this mutagenic process.

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