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Abstract
LMNA encodes nuclear Lamin A/C that tethers
lamina-associated domains (LADs) to the nuclear periphery. Mutations in
LMNA cause degenerative disorders including the premature
aging disorder Hutchinson-Gilford progeria, but the mechanisms are unknown. We
report that Ser22-phosphorylated (pS22) Lamin A/C was localized to the nuclear
interior in human fibroblasts throughout the cell cycle. pS22-Lamin A/C
interacted with a subset of putative active enhancers, not LADs, at locations
co-bound by the transcriptional activator c-Jun. In progeria-patient
fibroblasts, a subset of pS22-Lamin A/C-binding sites were lost whereas new
pS22-Lamin A/C-binding sites emerged in normally quiescent loci. New pS22-Lamin
A/C binding was accompanied by increased histone acetylation, increased c-Jun
binding, and upregulation of nearby genes implicated in progeria
pathophysiology. These results suggest that Lamin A/C regulates gene expression
by enhancer binding. Disruption of the gene regulatory rather than LAD tethering
function of Lamin A/C may underlie the pathogenesis of disorders caused by
LMNA mutations. Nuclear lamins bind heterochromatin domains at the nuclear periphery.
Ikegami et al. now show that a phosphorylated form of nuclear lamins bind to
active enhancers in euchromatin in the nuclear interior. They provide evidence
that suggests disruption of phosphorylated lamin function at enhancers
contributes to the pathogenesis of progeria.