GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331509/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331509GEOGSEfalseLimb cell-fate commissioning is guided by widespread coordinated genome detachment from the nuclear lamina [CUT&Tag]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.2026/07/15GSE331509GSM9748327GSM9748326GSM9748329GSM9748328GSM9748323GSM9748367GSM9748366GSM9748322GSM9748369GSM9748325GSM9748324GSM9748368GSM9748363GSM9748362GSM9748321GSM9748365GSM9748320GSM9748364GSM9748361GSM9748360GSM9748338GSM9748337GSM9748339GSM9748378GSM9748334GSM9748333GSM9748377GSM9748336GSM9748335GSM9748379GSM9748330GSM9748374GSM9748373GSM9748332GSM9748376GSM9748375GSM9748331GSM9748370GSM9748372GSM9748371GSM9748349GSM9748348GSM9748345GSM9748344GSM9748347GSM9748346GSM9748341GSM9748340GSM9748343GSM9748342GSM9748381GSM9748380GSM9748359GSM9748356GSM9748355GSM9748358GSM9748357GSM9748352GSM9748351GSM9748354GSM9748353GSM974835024247331509Mus musculus