The segregation of heterochromatin domains (LADs) at the nuclear periphery by the nuclear lamina, composed by polymerized nuclear Lamin A/C, provides a longstanding paradigm for the control of gene expression and for the mechanisms underlying Lamin-A/C-associated disorders, including progeria and cardiomyopathy. Here, we provide evidence supporting a novel paradigm that Lamin A/C functions as a transcription factor in the nuclear interior. We discovered that Ser22-phosphorylated Lamin A/C (pS22-Lamin A/C), required for lamin depolymerization during mitosis, populated the nuclear interior throughout the cell cycle. pS22-Lamin A/C ChIP-deq demonstrated localization at a large subset of putative active enhancers, not LADs. pS22-Lamin A/C-binding sites were co-occupied by the transcriptional activator c-Jun. In progeria patient-derived fibroblasts, a subset of pS22-Lamin A/C-binding sites were lost whereas new pS22-Lamin A/C-binding sites emerged. New pS22-Lamin A/C binding was accompanied by increased histone acetylation and increased c-Jun binding, whereas loss of pS22-Lamin A/C-binding was accompanied by loss of histone acetylation and c-Jun binding. New pS22-Lamin A/C enhancer binding in progeria was associated with upregulated expression of genes implicated in progeria pathophysiology, including cardiovascular disease. In contrast, alteration of LADs in progeria-patient cells could not explain the observed gene expression changes. These results suggest that Lamin A/C regulates gene expression by enhancer binding in the nuclear interior, independent of its function at the nuclear lamina, providing a new paradigm for the pathogenesis of lamin-associated disorders. pS22-Lamin A/C was also present in the nuclear interior of adult mouse cardiomyocytes. Cardiomyocyte-specific deletion of
Lmna
encoding Lamin A/C in adult mice caused extensive transcriptional changes in the heart and dilated cardiomyopathy, without apparent reduction of nuclear peripheral Lamin A/C. Disruption of the gene regulatory rather than LAD tethering function of Lamin A/C may underlie the pathogenesis of disorders caused by
LMNA
mutations, including cardiomyopathy.
Promoter decoding of transcription factor dynamics involves a trade‐off between noise and control of gene expression