Junk DNA and the long non-coding RNA twist in cancer genetics

Abstract

The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual's susceptibility to cancer.

Figure 1. LncRNA functioning mechanisms via DNA-RNA interaction in cis or trans

(a) XIST loads onto the its own genomic locus via YY1, and recruits PCR2 complex to maintain repressive chromatin marked by H3K27me3 on the same X chromosome. (b) Enhancer RNAs transcribed from enhancer region maintain enhancer-promoter looping by recruiting mediators and transcription factors, and enhance transcription of neighboring mRNA genes. (c) PRNCR1, transcribed from 8q24, and PCGEM1, produced from 2q32, bind to androgen receptor (AR) to promote the chromatin status H3K4me3, and activate the AR-regulated genes located distant from their genomic loci. (d) HOTAIR recruits PRC2, and loads onto distant genomic loci to initiate repressive chromatin marked by H3K27me3, and block HOX gene transcription.

Figure 2. LncRNA and cancer predisposition SNPs on 8q24 genomic region

The 8q24.21 genomic region contains multiple lncRNA genes, located either upstream or downstream of the proto-oncogene MYC. Most of them have shown functional involvement in cancer, and some regulate MYC expression levels. The same region also features multiple cancer predisposition SNPs, either within or outside of the noncoding gene, suggesting a complex regulation network linking SNPs, lncRNAs and MYC.