Anti‐hsa‐miR‐59 alleviates premature senescence associated with Hutchinson‐Gilford progeria syndrome in mice. (16th November 2022)

• Record Type: Journal Article
• Authors: Hu, Qianying; Zhang, Na; Sui, Tingting; Li, Guanlin; Wang, Zhiyao; Liu, Mingyue; Zhu, Xiaojuan; Huang, Baiqu; Lu, Jun; Li, Zhanjun; Zhang, Yu
• Is Part Of: EMBO journal. Volume 42:Number 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-16
• Subjects: HGPS -- HMGA -- miR‐59 -- TFIIH; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2022110937
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Hutchinson‐Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence on gene expression, microRNAs (miRNAs) are attractive therapeutic tools to treat diseases. Here we identified that hsa‐miR‐59 (miR‐59) was markedly upregulated in HGPS patient cells and in multiple tissues of an HGPS mouse model ( Lmna G609G / G609G ), which disturbed the interaction between RNAPII and TFIIH, resulting in abnormal expression of cell cycle genes by targeting high‐mobility group A family HMGA1 and HMGA2. Functional inhibition of miR‐59 alleviated the cellular senescence phenotype of HGPS cells. Treatment with AAV9‐mediated anti‐miR‐59 reduced fibrosis in the quadriceps muscle, heart, and aorta, suppressed epidermal thinning and dermal fat loss, and yielded a 25.5% increase in longevity of Lmna G609G / G609G mice. These results identify a new strategy for the treatment of HGPS and provide insight into the etiology of HGPS disease. Synopsis: Cellular senescence in Hutchinson‐Gilford progeria syndrome (HGPS) is associated with downregulation of numerous genes. Identification of a miRNA upregulated in HGPS provides a potential therapeutic target, whose inhibition corrects cell cycle gene expression and pathogenesis in murine HPGS models. Hsa‐miR‐59 is upregulated in HGPS patient cells and multiple tissues of an HGPS mouse model (Lmna G609G/G609G ). Inhibition of hsa‐miR‐59 ameliorates the phenotype and extends longevity in Lmna G609G/G609G mice. Hsa‐miR‐59 promotes HGPS senescence by targeting HMGA1 and HMGA2. Decreased HMGA1/2 expression disturbs the interaction between RNAPII and TFIIH during HGPS senescence. HMGA1 corrects the abnormal expression of cell cycle genes by activating transcription initiation in HGPS. Abstract : Symptoms of aging in a mouse model of Hutchinson‐Gilford progeria syndrome are alleviated by inhibition of a newly found miRNA that interferes with cell cycle gene expression.