Many lncRNAs scaffold proteins to their targets. (A) Xist directs X chromosome inactivation across eutherian females. RNA fluorescence in situ hybridization (FISH) image shows focal retention of Xist transcripts (red; blue fluorescence demarks the nucleus). Transcript models from mouse and human are shown at bottom. The gray bar at the right marks the A-repeat region, with the 8 tandem A-repeats depicted above. Base pairing among the repeats is stochastic, and one of the specific conformations they adopt in vivo is shown at top. Xist remains cis-tethered to DNA (blue line) by binding the chromatin attachment factor HNRNPU. Binding to SPEN via the A-repeat domain followed by recruitment of histone deacetylase 3 (HDAC3), which catalyzes H3K4 demethylation leading to transcription machinery exclusion, enables transcription repression. Xist also binds HNRNPK, which facilitates scaffolding of epigenetic repressors such as PRC2, which deposits H3K27me3, leading to a transcription-repressive chromatin state. As Xist spreads in cis, it binds the lamin B receptor (LBR) to reposition its chromosome to the nuclear lamina, forming a compact repressive compartment.41 (B) lincRNA-EPS represses apoptotic/inflammatory response genes. RNA FISH image shows nuclear diffusion of lincRNA-EPS transcripts (red). Transcript models from mouse and human are shown at bottom. The gray bar marks a 3′ region with tandem CANACA repeats, depicted at top, which is not conserved in humans. Its predicted secondary structure, comprising the minimum free energy conformation identified by RNAfold, is shown at top. Under steady-state conditions, lincRNA-EPS binds HNRNPL via the CANACA-repeat domain and localizes to promoters of target genes, conferring a repressed chromatin state by promoting nucleosome occupancy upstream of their transcription start site. This basal transcription repression is lifted during infection/inflammatory responses. (C) LUNAR1 sustains oncogenic IGF1R activation in cis. Aberrantly activated NOTCH1 engages an enhancer element intronic to the IGF1R gene (orange) which activates LUNAR1, which in turn cooccupies this element and favors recruitment/retention of the transcription machinery, including Mediator, leading to enhanced activation of the IGF1R promoter and accumulation of additional IGF1R transcripts. (D) Bloodlinc potentiates the terminal erythropoiesis gene program. RNA FISH image shows nuclear diffusion of Bloodlinc molecules. Transcript models from mouse and human are shown at bottom. Bloodlinc diffuses from a super-enhancer domain to trans-loci encoding terminal erythropoiesis modulators, and binds HNRNPU as well as transcription coactivators/corepressors, mediating activation or repression of its targets.
