The differentiation of a pluripotent cell into a cell of a specialised lineage is accompanied by extensive changes in the expression of pluripotency and lineage-specific genes. Gene expression changes can be mediated by both chromatin modifications which make DNA more or less accessible to transcription factors and the physical movement of gene loci into silent or active nuclear compartments. Although changes in chromatin architecture are critical for gene expression control, we currently do not fully understand the role of chromatin dynamics and nuclear subcompartments in facilitating differentiation. The bulk of existing work has been generated through genome-wide techniques which, while able to reveal information about chromatin changes at high genomic resolution, fails to show both changes in 3D nuclear architecture and any subtle cell-to-cell variation. In this study we have carefully analysed high-resolution images of hundreds of individual cells in an attempt to assay the nuclear patterning of differently modified histones during early phases of pluripotency loss and the beginning stages of terminal lineage commitment. We documented dynamic changes of modified histones in different nuclear compartments in hESCs from both primed and “naïve” pluripotent states in addition to hESCs which are differentiating into trophoblast like (TBL) cells via supplementation with BMP4 while simultaneously inhibiting FGF signaling and the Activin/Nodal pathway. We report that two histone modifications, the di-methylation of histone 3 at lysine 9 (H3K9me2) and the acetylation of the histone variant H2A.Z (H2A.Z.ac) show movement towards and away from the nuclear periphery as hESCs transition from naïve to primed and differentiated states. Interestingly, we show that the HDAC complexes are key controlling factors in the establishment of chromatin environments, especially at the nuclear periphery, and that deacetylation is critical to the establishment of chromatin environments in differentiated cells.