How chromatin is packaged and organised within the nucleus over time has become a focus of recent research. Previous studies have shown that transcriptionally repressive heterochromatin is located at the periphery of the nucleus in lamina associated domains (LADs), which reorganise during differentiation and are marked by H3K9me2 modifications. However, it is unclear whether spatial reorganisation of nuclear peripheral heterochromatin is lineage-specific. Now, Jon Epstein and colleagues use H3K9me2 ChIP-seq to profile heterochromatin in P19 cells — a multipotent embryonal carcinoma cell line that can be induced down neurogenic or cardiogenic pathways using retinoic acid (RA) or DMSO, respectively. The study shows that genes that encode specific regulators of neurogenesis lose H3K9me2 modifications in response to RA-mediated differentiation, but those that encode cardiogenic factors remain in nuclear peripheral heterochromatin. Conversely, the opposite pattern is seen during cardiogenic differentiation. Finally, the authors use RNA-seq to correlate H3K9me2 modifications with gene expression. Indeed, neurogenic or cardiogenic transcription factors are upregulated in RA or DMSO-treated cells, respectively, whereas the expression of pluripotency markers such as Oct4 decreases. Taken together, these data show that the spatial repositioning of genomic loci away from the nuclear periphery is tightly controlled during cell lineage-specific fate decisions.