Figure 3. Noncoding RNA as an epigenetic layer and player.

A. LncRNAs can function to demarcate a nuclear subdomain by forming and “RNA cloud” (red), as seen for Xist and Kcnq1ot1, in order to coat chromosomes or genomic regions (blue) and regulate transcription [60]. Loci coated by the RNA cloud are most often silenced via recruitment of repressive chromatin complexes, but RNA clouds may also upregulate transcription [80]. B. LncRNAs (red) also act as molecular decoys either for DNA binding transcription factors (Gas5) or miRNAs (PTENP1). C. LncRNAs can have multiple protein interacting partners and thereby act as a molecular scaffold for larger complexes. D. In recent years a novel role for lncRNAs as epigenetic “players” has been described. Many lncRNAs were found to interact with the repressive chromatin modifier PRC2 [64, 79], and thereby regulate the chromatin structure of large domains, or even of whole chromosomes. Recently, activating lncRNAs were also described that bind to the Mediator complex and facilitate enhancer-promoter loops [3]. This function may potentially overlap with enhancer RNAs (eRNAs) which are transcribed bidirectionally from enhancers [68]. E. RNA also functions as an epigenetic “layer” by modifying the structure of the DNA or regulating sense transcription via antisense transcription. Such a role has been described at the neurodevelopmentally critical PWS/AS locus on chromosome 15q11-q13, where RNA:DNA hybrid (R-loop) formation at the Prader-Willi imprinting control region (PWS-ICR) protects against DNA methylation [8], and processive transcription to produce UBE3A-ATS silences paternal UBE3A in neurons [89]. Similarly, eRNAs may act as molecular signals to mark active enhancers in response to stimulation [68].