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Loss of the long non-coding RNA, Malat1, accelerates premature aging and mortality

ABSTRACT: Here we show that the 5’ end and 3’ end of Malat1 are dependently and independently expressed. Loss of 5’ Malat1 up-regulates Neat1 in cis, while loss of 3’ Malat1 globally regulated gene expression in trans. Furthermore, loss of 3’ Malat1 accelerates premature aging and shortens the lifespan in mice, but loss of 5’ Malat1 produces no phenotypic changes. Mechanistically, 3’ Malat1 exerts a tight regulation of P21 that is drastically up-regulated in brain and retina upon its deletion in mice. This is very likely mediated at two different levels. One is at the mRNA level since Malat1 interacts with hnRNP A1 and hnRNP A2/B1. This is independently of P53 since it is significantly decreased upon 3’ Malat1 KO, probably due to the down-regulation of hnRNP C which has been shown to maintain P53 mRNA stability in our cell line model. The other is at the protein level through NPM, which is significantly up-regulated in 3’ Malat1 KO and which was known to decrease P21 ubiquitination and hence stabilizing of P21. These observations reveal previously unknown functions of 3’ Malat in the brain and indicates the need for more detailed understanding of highly abundant conserved lncRNAs, such as Malat1, and alarms for detailed understanding before therapeutic targeting in the future.

ORGANISM(S): Mus musculus

PROVIDER: GSE130392 | GEO | 2022/07/02

REPOSITORIES: GEO

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