Long noncoding RNAs: cellular address codes in development and disease

Abstract

In biology as in real estate, location is a cardinal organizational principle that dictates the accessibility and flow of informational traffic. An essential question in nuclear organization is the nature of the address code--how objects are placed and later searched for and retrieved. Long noncoding RNAs (lncRNAs) have emerged as key components of the address code, allowing protein complexes, genes, and chromosomes to be trafficked to appropriate locations and subject to proper activation and deactivation. lncRNA-based mechanisms control cell fates during development, and their dysregulation underlies some human disorders caused by chromosomal deletions and translocations.

Figure 1. Comparison between a Roman city and the cell nucleus reveals the importance of spatial organization

(A) Depiction of the basic features of a Roman city. City walls delimit the city, with gates at the two main roads that intersect at the center of the city. The Forum was the business and political center of the city and many buildings provided specific functions essential for city life. (B) Schematic representation of the typical nuclear organization during interphase. Each chromosome occupies a discrete territory. Euchromatin localizes to the interior regions of the nucleus and the densely compacted Heterochromatin localizes near the nuclear envelope. Many specialized functions are executed in distinct regions in the nucleus, known as nuclear bodies. One example is the nucleolus, where ribosomes are assembled. Adapted from (Solovei et al., 2009).

Figure 2. Functional modules of IncRNAs in the nucleus

(A) The act of transcription at noncoding regions can modulate gene expression through the recruitment of chromatin modifiers to the site of transcription. These complexes can create a local chromatin environment that facilitates or blocks the binding of other regulators. (B) LncRNAs can function in cis, recruiting protein complexes to their site of transcription, thus creating a locus specific address. Cells can use this mechanism to repress gene or activate gene expression. (C) LncRNAs can function in trans and recruit protein complexes to chromatin loci away from their site of transcription. (D) LncRNAs can bind and sequester transcription factors away from their target chromosomal regions.

Figure 3. Schematic representation of the cell nucleus showing the nucleolus and chromosomal territories

(A) Protein components of the Paraspeckle diffused throughout the nucleoplasm aggregate upon the transcription of NEAT1 forming the Paraspeckle nuclear domain. (B) Pc2 differentially binds MALAT1/NEAT2 or TUG1 depending on methylation status. Methylated Pc2 interacts with TUG1, bringing associated growth control genes to a repressive environment; the polycome body (PcG). Unmethylated Pc2 interacts with MALAT1/NEAT2 at the Interchromatin granule (ICG), where gene expression is permitted. (C) Expression of IncRNAs with snoRNA ends from the Prader-Willi syndrome locus function as sinks for the FOX2 protein, leading to a redistribution of this splicing factor in this nuclear region. (D) In response to cellular stress, transcription of specific IGSRNAs leads to the retention of targeted proteins at the nucleolus. Different types of stress lead to the retention of different proteins, through the expression of specific noncoding RNAs.

Figure 4. LncRNAs regulate gene expression in the cytoplasm

(A) The IncRNA TINCR interacts with STAU1 and target mRNAs containing the TINCR box motif, promoting their stability. (B) LncRNAs of the 1/2-sbsRNAs class hybridize with 3’ UTR containing Alu elements, and promotes the degradation of these target mRNAs. (C) Under stress conditions the IncRNA Antisense to Uchl1 moves from the nucleus to the cytoplasm and binds the 5’ end of the Uchl1 mRNA to promote its translation under stress conditions. (D) LincRNA-p21 interacts with and targets RcK to mRNAs resulting in translation inhibition.