miR-376a-3p and miR-376b-3p overexpression in Hutchinson-Gilford progeria fibroblasts inhibits cell proliferation and induces premature senescence

Diane Frankel (1, 2) , Valerie Delecourt (1) , Elva-María Novoa-Del-Toro (1) , Jérôme Robin-Ducellier (1) , Coraline Airault (1) , Catherine Bartoli (1) , Aurelie Carabalona (3, 1) , Sophie Perrin (4) , Kilian Mazaleyrat (1) , Annachiara de Sandre-Giovannoli (1, 5, 6) , Frédérique Magdinier (1) , Anaïs Baudot (1) , Nicolas Levy (1, 5) , Elise Kaspi (1, 2) , Patrice Roll (1, 2)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM]
3 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
4 ProGeLife [Marseille]
5 Département de génétique médicale [Hôpital de la Timone - APHM]
6 CRB TAC - Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM]

Hutchinson-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.

Mots clés: Biological sciences; Molecular biology; Cell biology

Domaines: Neurosciences [q-bio.NC]

Diane Frankel, Valerie Delecourt, Elva-María Novoa-Del-Toro, Jérôme Robin-Ducellier, Coraline Airault, et al.. miR-376a-3p and miR-376b-3p overexpression in Hutchinson-Gilford progeria fibroblasts inhibits cell proliferation and induces premature senescence. iScience, 2022, 25 (2), pp.103757. ⟨10.1016/j.isci.2022.103757⟩. ⟨hal-03788582⟩