06 October 2022

Target RNA in progeria

Progeroid syndromes (Werner syndrome, Hutchinson-Guilford syndrome) are a group of rare genetic disorders that cause signs of premature aging in children and young people. Patients develop conditions and diseases usually associated with aging – heart disease, cataract, type II diabetes, osteoporosis.

This aging is characterized by a progressive violation of the packaging of genetic material and tissue-specific genetic program. Researchers from the King Abdullah University of Science and Technology have identified a new target for the treatment of progeroid syndromes by preventing the loss of nuclear architecture.

17-20% of the mammalian genome is occupied by poorly understood non-coding long repeating RNA sequences (long interspersed nuclear element-1 RNA, LINE-1 RNA), the functions of which are largely unknown. They remain inactive due to the dense packing of DNA in heterochromatin. There is evidence that the loss of heterochromatin in normal aging is associated with the activation of repetitive RNA sequences. Based on theoretical considerations, the group suggested that the molecular interaction between LINE-1 RNA and a specific enzyme histone-lysine N-methyltransferase (SUV39H1), which controls the stability of heterochromatin, may be the cause of premature aging in progeria.

Sequencing of the genome of cells of patients with progeroid syndromes demonstrated increased expression of LINE-1 RNA. Further tests showed that this increased expression of LINE-1 RNA was responsible for the deactivation of SUV39H1, which led to the loss of heterochromatin and changes in the activity of genes that cause cell aging.

The researchers were able to block the expression of LINE-1 RNA and reverse the aging process in cells taken from patients with progeroid syndromes and in mouse models of Hutchinson-Guilford syndrome. They did this using short synthetic nucleotide chains – antisense oligonucleotides that lead to degradation of LINE-1 RNA. Depletion of LINE-1 RNA restored the epigenetic tags of heterochromatin and reduced the expression of genes associated with aging, which led to an increase in life expectancy.

Further studies are needed to determine whether other mechanisms acting in parallel with the inhibition of SUV39H1 may disrupt the stability of heterochromatin in progeroid syndromes.

Given the similarities between progeroid syndromes and diseases associated with natural aging, targeting LINE-1 RNA may be an effective way to treat both progeroid syndromes and age-related diseases, including neurodegenerative, metabolic and cardiovascular disorders and cancer.

Article by F.Della Valle et al. LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes published in the journal Science Translational Medicine.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of King Abdullah University of Science and Technology: Finding an RNA target and tool to fight premature aging.

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