LAP2alpha facilitates myogenic gene expression by preventing nucleoplasmic lamin A/C from spreading to active chromatin regions

Abstract

Abstract A-type lamins form a filamentous meshwork beneath the nuclear membrane that anchors large heterochromatic genomic regions at the nuclear periphery. A-type lamins also exist as a dynamic, non-filamentous pool in the nuclear interior, where they interact with lamin-associated polypeptide 2 alpha (LAP2α). Both proteins associate with largely overlapping euchromatic genomic regions in the nucleoplasm, but the functional significance of this interaction is poorly understood. Here, we report that LAP2α relocates towards regions containing myogenic genes in the early stages of muscle differentiation, possibly facilitating efficient gene regulation, while lamins A and C mostly associate with genomic regions away from these genes. Strikingly, upon depletion of LAP2α, A-type lamins spread across active chromatin and accumulate at regions of active H3K27ac and H3K4me3 histone marks in the vicinity of myogenic genes whose expression is impaired in the absence of LAP2α. Reorganization of A-type lamins on chromatin is accompanied by depletion of the active chromatin mark H3K27ac and a significantly impaired myogenic differentiation. Thus, the interplay of LAP2α and A-type lamins is crucial for proper positioning of intranuclear lamin A/C on chromatin to allow efficient myogenic differentiation.