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Deregulated miRNAs in Hutchinson-Gilford Progeria Syndrome: Unraveling the Link of miRNAs to normal and premature aging.

ABSTRACT: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal disorder causing premature aging, affecting about 1 in 4–8 million births. Most cases are linked to a mutation in the LMNA gene, which leads to the production of a defective protein called progerin. In HGPS, progerin expression leads to the loss of heterochromatin, which significantly alters gene expression. This alteration particularly affects RNA polymerase II, a crucial enzyme in transcribing primary-miRNA (pri-miRNA) transcripts. As a result, changes in RNA polymerase II activity lead to aberrant levels of miRNAs that are a common feature in age-related diseases, including HGPS, where they contribute to the disease phenotype and progression. In this study, we investigate the molecular mechanisms underlying HGPS and normal aging using global miRNA sequencing to identify differentially expressed miRNAs associated with aging and/or premature aging conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282307 | GEO | 2025/12/02

REPOSITORIES: GEO

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Recapitulation of human premature aging by using iPSCs from Hutchinson-Gilford progeria syndrome

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Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a segmental premature aging disorder caused by the accumulation of the truncated form of Lamin A known as Progerin within the nuclear lamina. Cellular hallmarks of HGPS include nuclear blebbing, loss of peripheral heterochromatin, defective epigenetic inheritance, altered gene expression, and senescence. To model HGPS using iPSCs, detailed genome-wide and structural analysis of the epigenetic landscape is required to assess the initiation and progression of the disease. We generated a library of iPSC lines from fibroblasts of HGPS patients and controls, including one family trio. Our microarray results suggest that despite the presence of defects associated with Progerin in the nuclear lamina including structural defects, senescence and abnormal epigenetic marks, HGPS fibroblasts can be reprogrammed into iPSCs with transcriptomes that are essentially identical to control iPSCs and hESCs.

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Project description:Regular nuclear structure is critical for genome maintenance and proper gene expression, disorder of which has a causal role in aging. Accumulation of Progerin in Hutchinson-Gilford progeria syndrome (HGPS) disrupts the integrity of nuclear lamina and causes nuclear structure abnormalities, leading to premature aging. However, the nuclear structure/function relationships in HGPS cells have not been well addressed, and roles of nuclear sub-compartments for HGPS pathogenesis are rarely reported. Here, evidence reveals that classical dot-like PML nuclear bodies (PML NBs) are reorganized into thread-like morphology in HGPS cells, and these irregular NBs are strongly associated with cell senescence. We demonstrate that farnesylated Progerin interacts with PML isoform 2 specifically, which accounts for the formation of thread-like PML NBs. Moreover, our findings uncover that irregular PML NBs perturb NBs-associated DNA repair and gene transcription, thereby promoting HGPS cell senescence. Thus, our work helps to clarify the roles of nuclear structure and sub-compartments such as PML NBs in cell aging, and evidence presented in this study strongly support that thread-like PML NBs could be a novel biomarker of human cell senescence.

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