H2A.Z-nucleosomes participate in both euchromatic and heterochromatic scenarios and it has proven difficult to reveal correlation of the disparate roles with the stability features imparted by H2A.Z on the nucleosomes. Using a robust in situ assay of nucleosome stability and cell lines expressing only engineered forms of the variant we show that a major fraction of H2A.Z is released from the nucleosomes of peripheral heterochromatin at unusually high salt concentration, an observation reproduced with reconstituted nucleosomes. In cells expressing H2A.Z lacking its C-terminal tail, or upon addition of the tail peptide to control nuclei, canonical stability features are restored, the peripheral heterochromatin becomes dispersed and an increase of nuclease sensitivity, mainly at lamina-associated domains, ensues. Binding of the peptide to nucleosomes was detected by fluorescence correlation spectrometry. The peptide, when introduced into live cells, also induces reorganization of chromatin and decreases MYC expression, offering means for targeted epigenetic modulation.