ATAC-seq reported in "Phosphorylated Lamin A/C in the nuclear interior binds active enhancers associated with abnormal transcription in progeria"

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 presents a novel mechanism for disorders caused by LMNA mutations. Overall design: The aims of this project are to 1) identify the locations of the human genome associated with Ser22-phosphorylated LMNA by ChIP-seq in normal and progeria-patient cells; 2) define the chromatin characteristics of Ser22-phosphorylated LMNA-associated sites by histone ChIP-seq and ATAC-seq; and 3) identify genes dysregulated in progeria-patient cells by RNA-seq.