been found to carry out direct allosteric modulation of enhancer-bound CBP/p300
HAT complexes to the opposite end, that of gene activation. eRNAs can allosterically stimulate CBP HAT activity to increase both enhancer and target promoter
H3K27ac levels and epigenetically activate target gene transcription [21] (Fig. 1b).
2.2 LncRNA Epitranscriptomics
Just as the field of epitranscriptomics, the study of post-transcriptional modifications
of RNA molecules is beginning to expand, so too has attention turned to chemical
modifications of lncRNAs. Although several instances of such lncRNA editing have
already been reported, very little is known about their effects on lncRNA function
[22]. In the best-characterised lncRNA editing scenario to date, MethyltransferaseLike 3 (METTL3) interacts with Xist RNA via Spen family RNA-binding motif
proteins 15 and 18 (RBMP15, RBMP18) to carry out N
6 -adenosine methylation
(m
6 A) of Xist. (m
6 A)-Xist is then recognised by YTH domain containing
1 (YTHDC1) [23]. Despite its necessity, it is unclear how Xist-mediated recruitment
of YTHDC1, as facilitated by the Xist modification pathway described, contributes
to the Xist-directed epigenetic repression of gene transcription during XCI [23].
2.3 Nuclear Architecture and 3D Genome Structure
Recent efforts to characterise the Xist interactome during XCI have also yielded
insights into how the higher-order chromatin structure of the Xi is rearranged and
compacted. The Xa forms a 3D structural arrangement shaped by various topologically associating domains (TADs). During the process of XCI, Xist first silences
and compacts the chromatin surrounding the Xic locus and then spreads to other
nearby sites of the designated Xi to form the transcriptionally silent inactive X
territory that expands as Xist transcripts spread and pull increasingly distant Xi
regions into the inactive X territory as do other chromosomes [24]. This process
culminates with the formation of two compacted Xi megadomains that are tethered
to the nuclear lamina [25] and several megaloops that escape Xist-mediated
compaction to form transcriptionally active foci in the nuclear core [9] (Fig. 1c).
One such XCI escape locus, Firre, expresses another lncRNA that sculpts 3D
chromosomal conformation. Firre transcripts are anchored by SAFA to both cis and
trans chromatin sites in a multivalent manner to bring specific loci from various
chromosomes into proximity with each other. Together they form a distinct Firrescaffolded nuclear subcompartment that is associated with the co-regulation of genes
involved in several pluripotency pathways, chief among which are adipogenesis
and electron transport chain-mediated energy metabolism [26].
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
407
HAT complexes to the opposite end, that of gene activation. eRNAs can allosterically stimulate CBP HAT activity to increase both enhancer and target promoter
H3K27ac levels and epigenetically activate target gene transcription [21] (Fig. 1b).
2.2 LncRNA Epitranscriptomics
Just as the field of epitranscriptomics, the study of post-transcriptional modifications
of RNA molecules is beginning to expand, so too has attention turned to chemical
modifications of lncRNAs. Although several instances of such lncRNA editing have
already been reported, very little is known about their effects on lncRNA function
[22]. In the best-characterised lncRNA editing scenario to date, MethyltransferaseLike 3 (METTL3) interacts with Xist RNA via Spen family RNA-binding motif
proteins 15 and 18 (RBMP15, RBMP18) to carry out N
6 -adenosine methylation
(m
6 A) of Xist. (m
6 A)-Xist is then recognised by YTH domain containing
1 (YTHDC1) [23]. Despite its necessity, it is unclear how Xist-mediated recruitment
of YTHDC1, as facilitated by the Xist modification pathway described, contributes
to the Xist-directed epigenetic repression of gene transcription during XCI [23].
2.3 Nuclear Architecture and 3D Genome Structure
Recent efforts to characterise the Xist interactome during XCI have also yielded
insights into how the higher-order chromatin structure of the Xi is rearranged and
compacted. The Xa forms a 3D structural arrangement shaped by various topologically associating domains (TADs). During the process of XCI, Xist first silences
and compacts the chromatin surrounding the Xic locus and then spreads to other
nearby sites of the designated Xi to form the transcriptionally silent inactive X
territory that expands as Xist transcripts spread and pull increasingly distant Xi
regions into the inactive X territory as do other chromosomes [24]. This process
culminates with the formation of two compacted Xi megadomains that are tethered
to the nuclear lamina [25] and several megaloops that escape Xist-mediated
compaction to form transcriptionally active foci in the nuclear core [9] (Fig. 1c).
One such XCI escape locus, Firre, expresses another lncRNA that sculpts 3D
chromosomal conformation. Firre transcripts are anchored by SAFA to both cis and
trans chromatin sites in a multivalent manner to bring specific loci from various
chromosomes into proximity with each other. Together they form a distinct Firrescaffolded nuclear subcompartment that is associated with the co-regulation of genes
involved in several pluripotency pathways, chief among which are adipogenesis
and electron transport chain-mediated energy metabolism [26].
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
407