non-coding transcript of over 200 nt, can exceed 10Knt in length [2]. LncRNAs are
further stratified into long intergenic ncRNA (lincRNAs), transcribed ultraconserved
regions (T-UCRs), natural antisense transcripts (NATs) and large intronic ncRNAs,
among other groups. Although few of the nearly 60,000 human lncRNA “genes” [3]
have been well-characterised, they have been implicated in a diverse array of
molecular and biological processes, of which we outline herein their roles in
the epigenetic regulation of gene expression, nuclear architecture, alternative splicing and RNA-RNA crosstalk [4]. We also provide an overview of key discoveries
that reveal how some lncRNAs can misguide epigenetic factors to generate cancerpromoting epigenetic alterations, while others act as barriers to neoplastic growth,
and we describe how lncRNAs differentially expressed in cancer can serve as
biomarkers for patient prognosis and how they can influence the sensitivity of
tumours to anticancer therapy. Finally, we outline recent innovative studies that
have brought the prospect of therapeutically targeting oncogenic lncRNAs closer
to fruition.
2 lncRNAs in Epigenetic Processes
A central focus of lncRNA research is the hypothesis that lncRNAs directly interact
with epigenetic factors to guide them to specific target loci, specifying their sites
of reading, writing and erasure of epigenetic marks. In this capacity, they are
thought to function as RNA scaffolds of specific and context-dependent chromatin
regulatory complexes to fine-tune the chromatin landscape of any given genetic
locus or genomic region [5]. This section will outline how the concept of the
epigenetic interface with lncRNAs emerged, how this interface may shape the
epigenetic landscape and the challenges and discrepancies that confront us in
defining these regulatory principals.
2.1 Histone Modification and Transcriptional Regulation
The idea that lncRNAs influence the epigenetic control of gene expression emerged
on the back of major breakthroughs in characterising the process of X-chromosome
inactivation (XCI) that were made during the 1990s and early 2000s [6]. Recent
efforts to comprehensively characterise Xist-interacting proteins using novel biochemical approaches to study protein-RNA interactions have led to the development
of a refined model of how Xist enacts XCI. Accordingly, Xist interacts with Xi
loci via the DNA-/RNA-binding protein SAFA and recruits histone deacetylase
3 (HDAC3) and the SMRT complex via SHARP to initiate transcriptional silencing.
Subsequent recruitment of Polycomb Repressive Complexes 1 and 2 (PRC1/PRC2)
by Xist then serves to consolidate gene repression and chromatin compaction [7–9].
404
D. Hanly et al.
further stratified into long intergenic ncRNA (lincRNAs), transcribed ultraconserved
regions (T-UCRs), natural antisense transcripts (NATs) and large intronic ncRNAs,
among other groups. Although few of the nearly 60,000 human lncRNA “genes” [3]
have been well-characterised, they have been implicated in a diverse array of
molecular and biological processes, of which we outline herein their roles in
the epigenetic regulation of gene expression, nuclear architecture, alternative splicing and RNA-RNA crosstalk [4]. We also provide an overview of key discoveries
that reveal how some lncRNAs can misguide epigenetic factors to generate cancerpromoting epigenetic alterations, while others act as barriers to neoplastic growth,
and we describe how lncRNAs differentially expressed in cancer can serve as
biomarkers for patient prognosis and how they can influence the sensitivity of
tumours to anticancer therapy. Finally, we outline recent innovative studies that
have brought the prospect of therapeutically targeting oncogenic lncRNAs closer
to fruition.
2 lncRNAs in Epigenetic Processes
A central focus of lncRNA research is the hypothesis that lncRNAs directly interact
with epigenetic factors to guide them to specific target loci, specifying their sites
of reading, writing and erasure of epigenetic marks. In this capacity, they are
thought to function as RNA scaffolds of specific and context-dependent chromatin
regulatory complexes to fine-tune the chromatin landscape of any given genetic
locus or genomic region [5]. This section will outline how the concept of the
epigenetic interface with lncRNAs emerged, how this interface may shape the
epigenetic landscape and the challenges and discrepancies that confront us in
defining these regulatory principals.
2.1 Histone Modification and Transcriptional Regulation
The idea that lncRNAs influence the epigenetic control of gene expression emerged
on the back of major breakthroughs in characterising the process of X-chromosome
inactivation (XCI) that were made during the 1990s and early 2000s [6]. Recent
efforts to comprehensively characterise Xist-interacting proteins using novel biochemical approaches to study protein-RNA interactions have led to the development
of a refined model of how Xist enacts XCI. Accordingly, Xist interacts with Xi
loci via the DNA-/RNA-binding protein SAFA and recruits histone deacetylase
3 (HDAC3) and the SMRT complex via SHARP to initiate transcriptional silencing.
Subsequent recruitment of Polycomb Repressive Complexes 1 and 2 (PRC1/PRC2)
by Xist then serves to consolidate gene repression and chromatin compaction [7–9].
404
D. Hanly et al.