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Summary Epigenetic regulation serves as the basis for stem cell differentiation into distinct cell types, but it is unclear how global epigenetic changes are regulated during this process. Here, we tested the hypothesis that global chromatin organization affects the lineage potential of stem cells and that manipulation of chromatin dynamics influences stem cell function. Using nuclease sensitivity assays, we found a progressive decrease in chromatin digestion among pluripotent embryonic stem cells (ESCs), multipotent hematopoietic stem cells (HSCs), and mature hematopoietic cells. Quantitative high-resolution microscopy revealed that ESCs contain significantly more euchromatin than HSCs, with a further reduction in mature cells. Increased cellular maturation also led to heterochromatin localization to the nuclear periphery. Functionally, prevention of heterochromatin formation by inhibition of the histone methyltransferase G9A resulted in delayed HSC differentiation. Our results demonstrate global chromatin rearrangements during stem cell differentiation and that heterochromatin formation by H3K9 methylation regulates HSC differentiation., Graphical Abstract, Highlights • Nuclease sensitivity decreases progressively with stem cell differentiation • Distinct chromatin architecture is apparent in cells of different lineage potential • Stem cell differentiation leads to perinuclear heterochromatin localization • G9a-mediated heterochromatin formation facilitates stem cell differentiation, Forsberg and colleagues use a variety of approaches to investigate global chromatin structure and architecture in pluripotent, multipotent, and differentiated cells. They show that progressive changes in nuclease sensitivity, chromatin condensation, and heterochromatin localization correlate with the lineage potential of embryonic and adult stem cells and committed cells. Functionally, inhibition of heterochromatin formation delayed hematopoietic stem cell differentiation. These data provide new insights on the epigenetic regulation of stem cell lineage potential and differentiation.