Kesler Benjamin K, Adams John, Neuert Gregor
Department of Molecular Physiology and Biophysics, Basic Sciences, School of Medicine, Vanderbilt University, Nashville, TN, USA.
Department of Pharmacology, Basic Sciences, School of Medicine, Vanderbilt University, Nashville, TN, USA.
Nat Commun. 2025 May 7;16(1):4223. doi: 10.1038/s41467-025-59496-6.
Long noncoding RNAs (LncRNAs) are increasingly recognized as being involved in human physiology and diseases, but there is a lack of mechanistic understanding for the majority of lncRNAs. We comparatively test proposed mechanisms of antisense lncRNA regulation at the X-chromosome Inactivation (XCI) locus. We find that due to stochasticity in transcription, different mechanisms based on the act of transcription regulate Xist and Tsix at different levels of nascent transcription. At medium levels, RNA polymerases transcribe Xist and Tsix on each strand at the same transcription site and deposit significant amounts of the histone mark H3K36me3, which inhibits Xist. At high levels of nascent transcription, many RNA polymerases transcribe Xist or Tsix resulting in transcriptional interference. Therefore, lncRNA expression variability is not just a quirk of transcription but an important aspect of regulation that allows multiple mechanisms to be employed by the same gene locus within the same cell population.
长链非编码RNA（LncRNAs）越来越被认为参与人类生理和疾病过程，但对于大多数LncRNAs缺乏机制上的理解。我们比较测试了X染色体失活（XCI）位点反义LncRNA调控的提出机制。我们发现，由于转录的随机性，基于转录行为的不同机制在新生转录的不同水平上调控Xist和Tsix。在中等水平时，RNA聚合酶在每条链的同一转录位点转录Xist和Tsix，并沉积大量组蛋白标记H3K36me3，这会抑制Xist。在新生转录的高水平时，许多RNA聚合酶转录Xist或Tsix，导致转录干扰。因此，LncRNA表达变异性不仅仅是转录的一个怪癖，而是调控的一个重要方面，它允许同一细胞群体中的同一基因座采用多种机制。
