Limb cell-fate commissioning is guided by widespread coordinated genome detachment from the nuclear lamina [CUT&Tag]

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.