Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element

Abstract

Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements.

The how and why of lncRNA function: An innate immune perspective

“…LncRNAs can span large stretches of DNA sequence and can contain important regulatory regions, such as enhancers, that are functionally independent of the lncRNA product [182]. LncRNA promoters have been proposed to also function as enhancers, promoting the recruitment of transcriptional-activating factors that can affect the local nucleosome environment and ultimately the expression of neighboring genes [118,183,184].…”

Mechanistic diversification of XIST regulatory network in mammals

“…Particularly relevant are the lncRNA genes hosted within the Xic, 30 which have been linked to Xist regulation in the mouse: Tsix and Linx acts as major repressor of Xist expression while Jpx and Ftx acts as positive regulators. The mechanistic dissection of these Xiclinked and other lncRNA loci highlighted that their molecular function is not only mediated by the RNA molecule itself, but may also involve various entities such the act of transcription or key regulatory elements embedded within their locus (Cho et al, 2018;Engreitz et al, 2016;Furlan et al, 2018;Paralkar et al, 2016). For instance, the antisense transcription of the Tsix gene over the Xist locus contributes to the monoallelic repression of Xist (Navarro et al, 2005); Tsix transcription is itself controlled by the upstream lncRNA gene, Linx (Giorgetti et al, 2014;Nora et al, 2012).…”

Molecular functions and biological roles of long non‐coding RNAs in human physiology and disease

“…This notion is further supported by detailed studies of selected lncRNA loci that most likely confer their gene regulatory functions via the process of transcription (i.e. independent of the resulting transcript), via DNA enhancer elements within the lncRNA locus, or via promoter competition between the promoter of the lncRNA and the neighboring protein‐coding gene . Taking these findings into consideration, it becomes apparent that the molecular mechanism of each lncRNA locus needs to be carefully analyzed on a case‐by‐case basis before an actual functionality can be ascribed to the encoded RNA transcript.…”

“…independent of the resulting transcript), 8 via DNA enhancer elements within the lncRNA locus, 10 or via promoter competition between the promoter of the lncRNA and the neighboring protein-coding gene. 30 Taking these findings into consideration, it becomes apparent that the molecular mechanism of each lncRNA locus needs to be carefully HOTAIR indeed binds to chromatin within the HOXD cluster. 32 Although it has been initially proposed that HOTAIR directly binds to components of the polycomb repressor complex 2 (PRC2) and thereby recruits this complex to the HOXD locus, 31 PRC2 has been recently shown to be dispensable for HOTAIR-mediated silencing of a luciferase reporter locus, as well as a limited number of target loci in human cells.…”