GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE293nnn/GSE293961/primaryOK200OtherMus musculusOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293961GEOGSEfalseLimb cell-fate commissioning is guided by widespread coordinated genome detachment from the nuclear lamina [scDam&T-seq]Diverse forms of heterochromatin block inappropriate transcription and safeguard differentiation and cell identity. Yet, how and when heterochromatin is reconfigured to facilitate changes in cell-fate remains a key open question. Here, we address this by mapping a prevalent heterochromatic feature - genome-lamina interactions - relative to transcription in single-cells during mouse embryogenesis. We find that lamina-genome interactions remain relatively uniform following gastrulation but are extensively reconfigured during organogenesis in diverse tissues. Focusing on limb development, we demonstrate that genome-lamina interactions are selectively released at key developmental genes and their surrounding regulatory domains in early multipotent progenitors. Strikingly, this “lamina-release” often precedes later gene expression, suggesting it primes regulatory domains for future potential activation. Lamina-release also coincides with the putative binding of crucial limb transcription factors and so is closely intertwined with the regulatory machinery that drives limb formation. Conversely, we show that CTCF-defined boundaries of topologically-associated domains (TADs) constrains the spread of lamina-release at a limb gene locus. This ensures independent heterochromatin dynamics between neighbouring domains. Together, this suggests a previously unrecognised process where genome-lamina interactions are selectively dismantled at regulatory domains to transition loci toward more permissive chromatin states, thereby potentiating cell-type specific activation. Our work thus reveals how systematic heterochromatin reorganization links to developmental multipotency, providing mechanistic insight into how progenitors traverse diverse cell-fates in vivo.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 musculus