Long noncoding RNA functionality in imprinted domain regulation

Abstract

Genomic imprinting is a parent-of-origin dependent phenomenon that restricts transcription to predominantly one parental allele. Since the discovery of the first long noncoding RNA (lncRNA), which notably was an imprinted lncRNA, a body of knowledge has demonstrated pivotal roles for imprinted lncRNAs in regulating parental-specific expression of neighboring imprinted genes. In this Review, we will discuss the multiple functionalities attributed to lncRNAs and how they regulate imprinted gene expression. We also raise unresolved questions about imprinted lncRNA function, which may lead to new avenues of investigation. This Review is dedicated to the memory of Denise Barlow, a giant in the field of genomic imprinting and functional lncRNAs. With her passion for understanding the inner workings of science, her indominable spirit and her consummate curiosity, Denise blazed a path of scientific investigation that made many seminal contributions to genomic imprinting and the wider field of epigenetic regulation, in addition to inspiring future generations of scientists.

Fig 1. Imprinted domains and their long noncoding RNAs.

(A) Airn imprinted domain. (B) Kcnq1ot1 imprinted domain. (C) Nespas imprinted domain. (D) Snhg14 imprinted domain. (E) H19 imprinted domain. (F) Gtl2 imprinted domain. Note: The domain sizes indicated likely represent minimum lengths of the domains [10]. Imprinted protein-coding genes, which are expressed from one parental allele while the other copy is silent, reside in clusters or imprinted domains. Maternally expressed genes are represented by a red arrow and text, while paternally expressed genes are represented by a blue arrow and text. Nonimprinted genes, where both alleles are expressed, also localize to imprinted domains (black text). At least one lncRNA (wavy line) is present with a domain (dashed wavy line represents potential extension of a lncRNA transcript). Regulation of imprinting across an imprinted domain is through a cis-acting mechanism that is controlled by an ICR (large circles) and its associated lncRNA gene. Note: Some imprinted genes in these domain exhibit tissue-specific imprinted expression. The DNA methylated state of ICRs is depicted by large black circles, while an unmethylated ICR is denoted by white circles. Smaller circles represent methylation at secondary, somatic DMRs. Small ncRNAs housed within lncRNAs are depicted as diamonds for endogenous small interfering RNAs, arrowheads for microRNAs, and rhomboids for snoRNAs.

Fig 2. Function of long noncoding RNA genes.

(A-D) Expression of lncRNAs run transcription interference by directly suppressing transcription of a second gene in cis through multiple modes of action. (A) Promoter competition involves a strong promoter suppressing recruitment of the transcription initiation complex at a weaker promoter. (B) Promoter occlusion arises when transcription of a lncRNA blocks recruitment of the transcription initiation machinery at an overlapping promoter. (C) Dislodgement results when a lncRNA engages the elongation complex faster, leading to dislocation of the transcription complex at another transcript. (D) Collision involves the crash of two convergent elongation complexes between the lncRNA transcript and a second transcript, leading to premature termination of the latter. (E-H) Long RNAs themselves also have direct functions in gene regulation. (E) Long ncRNAs serve as a host for small ncRNAs which are excised from the lncRNA transcript. (F) Scaffold function refers to lncRNAs acting as the framework for RNA-binding proteins and modifier complexes interactions with DNA and chromatin to carry out their function. (G) lncRNAs can function as guides by aligning with specific DNA sequences though lncRNA and DNA pairing, attracting chromatin modifiers and directing chromatin modification to target sequences. (H) Decoy function involves lncRNAs acting as a sink or sponge to sequester proteins away from a target site.

Fig 3. Multiplicity of function for lncRNA genes and their transcripts at (A) the paternal Airn imprinted domain and (B) the maternal Gtl2 imprinted domain.

Note that some lncRNA functions may be part of the same mechanism, for example, scaffold and guide function, incorporating higher-order lncRNA structure as well.