RT Journal Article
SR Electronic
T1 Phosphorylated Lamin A targets active enhancers and is associated with abnormal transcriptional activation in progeria
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 682260
DO 10.1101/682260
A1 Kohta Ikegami
A1 Stefano Secchia
A1 Jason D. Lieb
A1 Ivan P. Moskowitz
YR 2019
UL http://biorxiv.org/content/early/2019/06/26/682260.abstract
AB LMNA encodes nuclear lamin A/C that tethers lamina-associated domains (LADs) to the nuclear lamina. Hutchinson-Gilford progeria is a premature aging disorder caused by heterozygous LMNA point mutations, however, the mechanism by which LMNA mutations cause progeria is unclear. We report that Ser22-phosphorylated LMNA (pS22-LMNA) was localized to the interior of the nucleus in human fibroblasts throughout the cell cycle. pS22-LMNA interacted with a specific subset of putative active enhancers, not LADs, primarily at locations co-bound by the transcriptional activator c-Jun. In progeria-patient fibroblasts, some pS22-LMNA-binding sites were lost whereas new pS22-LMNA-binding sites emerged at abnormal locations. New pS22-LMNA-binding in progeria cells was accompanied by increased H3K27 acetylation, increased c-Jun binding, and upregulated expression of genes implicated in coronary artery diseases, hypertension, and cardiomegaly, clinical components of progeria. Thus, pS22-LMNA bound to enhancers and progeria mutations affected pS22-LMNA-bound enhancer function. These observations expand the genomic role of LMNA to include direct enhancer binding and modulation, and introduce a novel molecular mechanism whereby LMNA mutation may contribute to disease distinct from LMNA’s role at the nuclear lamina.