Author Correction: Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A.
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ABSTRACT:
SUBMITTER: Kang SM
PROVIDER: S-EPMC8410774 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
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Author Correction: Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A.
Kang So-Mi SM Yoon Min-Ho MH Lee Su-Jin SJ Ahn Jinsook J Yi Sang Ah SA Nam Ki Hong KH Park Soyoung S Woo Tae-Gyun TG Cho Jung-Hyun JH Lee Jaecheol J Ha Nam-Chul NC Park Bum-Joon BJ
Scientific reports 20210901 1
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Project description:Mutations in the A-type lamins A and C, two major components of the nuclear lamina, cause a large group of phenotypically diverse diseases collectively referred to as laminopathies. These conditions often involve defects in chromatin organization. However, it is unclear whether A-type lamins interact with chromatin in vivo and whether aberrant chromatin-lamin interactions contribute to disease. Here, we have used an unbiased approach to comparatively map genome-wide interactions of gene promoters with lamin A and progerin, the mutated lamin A isoform responsible for the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) in mouse cardiac myoytes and embryonic fibroblasts. We find that lamin A-associated genes are predominantly transcriptionally silent and that loss of lamin association leads to the relocation of peripherally localized genes, but not necessarily to their activation. We demonstrate that progerin induces global changes in chromatin organization by enhancing interactions with a specific subset of genes in addition to the identified lamin A-associated genes. These observations demonstrate disease-related changes in higher order genome organization in HGPS and provide novel insights into the role of lamin-chromatin interactions in chromatin organization.
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Project description:BackgroundHutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Patients look healthy at birth, and symptoms typically emerge in the first or second year of life. Assessing the reversibility of progerin-induced damage and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies.MethodsWe used CRISPR-Cas9 technology to generate LmnaHGPSrev/HGPSrev (HGPSrev) mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time- and cell type-specific manner on Cre recombinase activation. We characterized the phenotype of HGPSrev mice and crossed them with Cre transgenic lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different disease stages as well as specifically in vascular smooth muscle cells and cardiomyocytes.ResultsLike patients with HGPS, HGPSrev mice appear healthy at birth and progressively develop HGPS symptoms, including failure to thrive, lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electrocardiographic anomalies, and precocious death (median lifespan of 15 months versus 26 months in wild-type controls, P<0.0001). Ubiquitous progerin suppression and lamin A restoration significantly extended lifespan when induced in 6-month-old mildly symptomatic mice and even in severely ill animals aged 13 months, although the benefit was much more pronounced on early intervention (84.5% lifespan extension in mildly symptomatic mice, P<0.0001, and 6.7% in severely ill mice, P<0.01). It is remarkable that major vascular alterations were prevented and lifespan normalized in HGPSrev mice when progerin suppression and lamin A restoration were restricted to vascular smooth muscle cells and cardiomyocytes.ConclusionsHGPSrev mice constitute a new experimental model for advancing knowledge of HGPS. Our findings suggest that it is never too late to treat HGPS, although benefit is much more pronounced when progerin is targeted in mice with mild symptoms. Despite the broad expression pattern of progerin and its deleterious effects in many organs, restricting its suppression to vascular smooth muscle cells and cardiomyocytes is sufficient to prevent vascular disease and normalize lifespan.
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