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- Aguado, J, et al.
(författare)
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Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4990-
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Tidskriftsartikel (refereegranskat)abstract
- Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.
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- Mata-Garrido, J, et al.
(författare)
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The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 6834-
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Tidskriftsartikel (refereegranskat)abstract
- Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the chromatin and alternative splicing regulator HP1γ is reduced in ulcerative colitis (UC). Accordingly, HP1γ gene inactivation in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis. In parallel, we find that its loss of function broadly increases splicing noise, favoring the usage of cryptic splice sites at numerous genes with functions in gut biology. This results in the production of progerin, a toxic splice variant of prelamin A mRNA, responsible for the Hutchinson-Gilford Progeria Syndrome of premature aging. Splicing noise is also extensively detected in UC patients in association with inflammation, with progerin transcripts accumulating in the colon mucosa. We propose that monitoring HP1γ activity and RNA splicing precision can help in the management of IBD and, more generally, of accelerated aging.
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| 9. |
- Revechon, G, et al.
(författare)
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Rare progerin-expressing preadipocytes and adipocytes contribute to tissue depletion over time
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 4405-
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Tidskriftsartikel (refereegranskat)abstract
- Accumulation of progerin is believed to underlie the pathophysiology of Hutchinson-Gilford progeria syndrome, a disease characterized by clinical features suggestive of premature aging, including loss of subcutaneous white adipose tissue (sWAT). Although progerin has been found in cells and tissues from apparently healthy individuals, its significance has been debated given its low expression levels and rare occurrence. Here we demonstrate that sustained progerin expression in a small fraction of preadipocytes and adipocytes of mouse sWAT (between 4.4% and 6.7% of the sWAT cells) results in significant tissue pathology over time, including fibrosis and lipoatrophy. Analysis of sWAT from mice of various ages showed senescence, persistent DNA damage and cell death that preceded macrophage infiltration, and systemic inflammation. Our findings suggest that continuous progerin expression in a small cell fraction of a tissue contributes to aging-associated diseases, the adipose tissue being particularly sensitive.
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