Emerging Functions of lncRNA Loci beyond the Transcript Itself

Abstract

Thousands of long noncoding RNAs (lncRNAs) are actively transcribed in mammalian genomes. This class of RNAs has important regulatory functions in a broad range of cellular processes and diseases. Numerous lncRNAs have been demonstrated to mediate gene regulation through RNA-based mechanisms. Simultaneously, non-functional lncRNA transcripts derived from the activity of lncRNA loci have been identified, which underpin the notion that a considerable fraction of lncRNA loci exert regulatory functions through mechanisms associated with the production or the activity of lncRNA loci beyond the synthesized transcripts. We particularly distinguish two main RNA-independent components associated with regulatory effects; the act of transcription and the activity of DNA regulatory elements. We describe the experimental approaches to distinguish and understand the functional mechanisms derived from lncRNA loci. These scenarios reveal emerging mechanisms important to understanding the lncRNA implications in genome biology.

Keywords: CRISPR-Cas9; chromatin; gene expression; long noncoding RNA.

Figure 1

Transcription from lncRNA loci remodels the chromatin landscape to induce gene regulation. (A) The act of transcription from lncRNA loci can induce gene silencing transcriptional interference, which leads to increasing nucleosome density downstream from transcribed lncRNA loci to physically prevent TF binding and avoid the access of RNAPII machinery. (B) Chromatin landscape can be reprogrammed by lncRNA transcription. Overlapped transcription drives the deposition of histone modifications and dynamic TF binding. (C) Local chromatin folding can be restructured through the dynamic binding of structural proteins. Transcription from ThymoD locus overlaps an enhancer element, which leads to CTCF/Cohesin binding to the enhancer and the downstream BCL11b promoter, allowing promoter-enhancer interaction throughout a chromatin looping structure. Transcription factors (TF), RNA polymerase II (RNAPII), histone methylation (Me), and histone acetylation (Ac).

Figure 2

Regulatory elements within lncRNA loci influence local gene regulation. (A) Promoters with enhancer-like activity and enhancer elements embedded in a particular lncRNA locus can induce a regulatory effect at distant genes. In some cases, neither the act of transcription nor the RNA transcript is necessary to distal gene regulation by the regulatory element. (B) LncRNA promoters can function as boundary elements to limit gene regulation by distal regulatory elements such as enhancers. PVT1 promoter prevents enhancer-promoter communication between intragenic enhancers within PVT1 lncRNA and MYC promoter. PVT1 promoter inactivation or mutation enables enhancer-promoter interactions and subsequent MYC overexpression.