Abstract
SummaryHutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder, in which an abnormal and toxic protein called progerin, accumulates in cell nuclei, leading to major cellular defects. Among them, chromatin remodeling drives gene expression changes, including miRNA dysregulation. In our study, we evaluated miRNA expression profiles in HGPS and control fibroblasts. We identified an enrichment of overexpressed miRNAs belonging to the 14q32.2-14q32.3 miRNA cluster. Using 3D FISH, we demonstrated that overexpression of these miRNAs is associated with chromatin remodeling at this specific locus in HGPS fibroblasts. We then focused on miR-376b-3p and miR-376a-3p, both overexpressed in HGPS fibroblasts. We demonstrated that their induced overexpression in control fibroblasts decreases cell proliferation and increases senescence, whereas their inhibition in HGPS fibroblasts rescues proliferation defects and senescence and decreases progerin accumulation. By targeting these major processes linked to premature aging, these two miRNAs may play a pivotal role in the pathophysiology of HGPS.
Highlights
Hutchinson-Gilford progeria syndrome (HGPS; OMIM #176670) is a rare genetic disease affecting approximately one in 8–10 million children
By focusing on miR-376b-3p and miR-376a-3p, two miRNAs from this cluster belonging to the same family, we discovered that they may play a role in cell proliferation and progerin clearance defects, leading to the premature senescence, which participates to HGPS pathophysiology
Profiling miRNA expression in HGPS fibroblasts We profiled the expression of 375 miRNAs using a quantitative RT-PCR (RT-qPCR) approach in five HGPS compared with five wild-type fibroblasts at passage 12 G 2 (P12 G 2)
Summary
Hutchinson-Gilford progeria syndrome (HGPS; OMIM #176670) is a rare genetic disease affecting approximately one in 8–10 million children. Classic HGPS is primarily caused by a de novo mutation (c.1824C > T, p.G608G) in exon 11 of the LMNA gene, encoding nuclear A-type lamins (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003). This mutation leads to the production of a 50 amino acid internally truncated, farnesylated prelamin A called progerin. This toxic protein affects the structure and functions of the nucleus and triggers multiple deleterious effects in HGPS cells. Progerin accumulates in cells, likely due to defective clearance, which might be linked with autophagy (Cenni et al, 2011; DuBose et al, 2018)
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