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

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. Comparison of 5' and 3' knockout of the lncRNA Malat1 in a mouse model.本研究证实，Malat1的5'端与3'端的表达兼具依赖调控与独立调控两种模式。敲除Malat1的5'端会在顺式（cis）层面上调Neat1的表达，而敲除Malat1的3'端则会在反式（trans）层面全局性调控基因的表达。此外，敲除Malat1的3'端会加速小鼠出现早衰表型并缩短其寿命，而敲除其5'端则不会引发任何可观测的表型变化。从机制层面分析，Malat1的3'端可对P21产生严格调控：在小鼠中敲除Malat1的3'端后，其大脑与视网膜中的P21表达会显著上调。该调控过程极可能通过两种不同层级实现：其一为mRNA层面，因Malat1可与hnRNP A1及hnRNP A2/B1相结合，且该调控过程不依赖于P53——在敲除Malat1的3'端后，P53的表达会显著下调，这可能是由于hnRNP C的表达被下调所致，而此前我们的细胞系模型实验已证实，hnRNP C可维持P53的mRNA稳定性。其二为蛋白质层面，该过程通过NPM介导：在敲除Malat1的3'端后，NPM的表达会显著上调，而已有研究表明NPM可降低P21的泛素化水平，进而稳定P21蛋白。上述研究结果揭示了Malat1的3'端在大脑中此前未被发现的功能，同时也表明，我们需要对Malat1这类高丰度且保守的长链非编码RNA（long non-coding RNA，lncRNA）开展更深入的机制解析，并警示我们在未来开展靶向治疗前，需先充分阐明这类RNA的生物学功能。本研究基于小鼠模型，对比了长链非编码RNA Malat1的5'端与3'端敲除后的表型差异。