Trends in Genetics
Volume 34, Issue 2, February 2018, Pages 142-157
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Review
Nuclear Long Noncoding RNAs: Key Regulators of Gene Expression

https://doi.org/10.1016/j.tig.2017.11.005Get rights and content

Highlights

A significant fraction of lncRNAs is retained in the nucleus, where several of them participate in vital nuclear processes, including chromatin organization, transcriptional and post-transcriptional gene expression, and nuclear structure organization.

The advent of new techniques, including chromatin isolation by RNA purification (CHIRP), capture hybridization analysis of RNA targets (CHART), RNA antisense purification (RAP), and mapping RNA genome interactions (MARGI), provides researchers more opportunity to study the chromatin-binding features of nuclear-retained lncRNAs, especially at the genomic level.

Many nuclear-retained lncRNAs are biomarkers of diagnosis and/or prognosis and/or therapeutic targets of diseases, including cancer.

The development of new computational tools and/or algorithms is required to determine the potential correlation between nuclear-retained lncRNA sequences and/or structures and their functions and/or localization.

A significant portion of the human genome encodes genes that transcribe long nonprotein-coding RNAs (lncRNAs). A large number of lncRNAs localize in the nucleus, either enriched on the chromatin or localized to specific subnuclear compartments. Nuclear lncRNAs participate in several biological processes, including chromatin organization, and transcriptional and post-transcriptional gene expression, and also act as structural scaffolds of nuclear domains. Here, we highlight recent studies demonstrating the role of lncRNAs in regulating gene expression and nuclear organization in mammalian cells. In addition, we update current knowledge about the involvement of the most-abundant and conserved lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), in gene expression control.

Section snippets

Overview of Nuclear-Enriched lncRNAs

It is estimated that approximately 75% of the human genome is utilized for generating transcripts with no apparent protein-coding potential, and these transcripts are classified as ncRNAs [1]. lncRNAs are grouped into transcripts that are >200-nucleotides long. The human genome is estimated to contain approximately 16 000 lncRNA genes (statistics from Human GENCODE Release version 27). A significant fraction of nuclear localized lncRNAs are transcribed by RNA polymerase II (RNA Pol II), and

Role of Nuclear-Retained lncRNAs in Chromatin Organization

A significant number of nuclear lncRNAs associate with chromatin and, thus, can be broadly classified as chromatin-enriched RNAs (cheRNAs) [11]. Some nuclear lncRNAs can influence chromatin architecture by interacting with chromatin-modulating proteins, such as Switch/sucrose nonfermentable (SWI/SNF) (see Glossary) or Polycomb repressive complex (PRC) subunits (Figure 1A), promoting their recruitment and/or association to chromatin, thereby controlling transcriptional activity 12, 13, 14, 15, 16

LncRNAs as Transcriptional Regulators

LncRNAs activate or repress transcription (summarized in Table 1) by acting locally [near the sites of their transcription (cis-regulation)] or distally [at sites that are located on other chromosomes (trans-regulation)] (Figure 2A). For instance, lncKdm2b sustains the maintenance of intestinal group 3 innate lymphoid cells (ILCs) by facilitating the transcriptional activation of a transcription factor (TF), zfp292 [12]. LncKdm2b facilitates the recruitment of chromatin organizer protein Satb1

LncRNAs as Post-Transcriptional Regulators

It is becoming increasingly evident that nuclear-restricted lncRNAs also regulate gene expression by influencing post-transcriptional events. The antisense-FGFR2 lncRNA promotes epithelial-specific alternative splicing of FGFR2 pre-mRNA [27]. AS-FGFR2 facilitates the recruitment of Polycomb-group proteins and histone demethylase KDM2a to the FGFR2 regulatory elements, thereby preventing the association and activity of a repressive-splicing adaptor complex that promotes mesenchymal-specific

Role of Nuclear-Retained lncRNAs in the Organization of Nuclear Structure

X-inactive specific transcript (Xist), one of the first functionally annotated nuclear lncRNAs, regulates dosage compensation by promoting X-chromosome inactivation (XCI). Xist is idealized by the scientific community as a perfect example of a nuclear lncRNA, because it coordinates several nuclear processes to achieve XCI. For example, discrete regions within Xist RNA are required for gene silencing, for the association of PRC2 to the inactive X chromosome (Xi), and for the localization of Xist

Role of MALAT1 in Gene Regulation

MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2), is perhaps the most-abundant (∼3000 copies/cell) nuclear-retained lncRNA. MALAT1 was initially identified as a prognostic marker for stage I lung adenocarcinoma [81]. MALAT1 is highly conserved among mammalian species 81, 82, 83, 84 and its orthologs have been identified in zebrafish, lizard, and Xenopus 85, 86.

MALAT1 is ubiquitously expressed in all tissues, but its levels are tightly regulated during certain physiological

Molecular Function of MALAT1

MALAT1 is almost strictly retained in the nucleus [105]. A large fraction of MALAT1 is localized within nuclear speckles 82, 83 and interacts with several of the speckle-enriched proteins, including splicing factors. Since MALAT1 preferentially localizes in nuclear speckles, NDs that are suggested to coordinate transcription and pre-mRNA processing, it is proposed that MALAT1 controls gene expression by modulating speckle-ascribed functions, including transcriptional and post-transcriptional

Involvement of MALAT1 in Cancer Progression and Metastasis

Ever since the initial identification of MALAT1 as a marker of metastatic lung cancer, a considerable number of studies have intimately linked MALAT1 to tumor progression and metastasis 139, 140. Elevated levels of MALAT1 are observed in a broad spectrum of cancers, and are frequently correlated with poor prognoses and chemo- or radiotherapy resistance in patients 114, 134, 141. Furthermore, alterations in the levels of MALAT1 in multiple cancer cell lines and in animal tumor models

Concluding Remarks

The human genome encodes approximately 16 000 lncRNAs, of which a significant fraction is retained in the nucleus. Nuclear lncRNAs are involved in almost all physiological and/or biological and disease-related processes. Most nuclear lncRNAs associate with chromatin and influence gene expression in a cis or trans fashion. Chromatin-associated lncRNAs control the recruitment or stabilization of various chromatin proteins or RNA-binding proteins to regulatory sequences within the gene or RNA,

Acknowledgments

We thank A. Lal and S.G. Prasanth for critical reading and suggestions. We thank J. Roy, S. Sudhakar, and S. Adusumilli for proof reading the manuscript. We thank Elsevier’s Illustration service (WebShop) for figure illustration. Work in the Prasanth lab is funded by NIH R01 (GM088252) and NSF EAGER (1723008) grants.

Glossary

Chromatin isolation by RNA purification (CHIRP), capture hybridization analysis of RNA targets (CHART), RNA antisense purification (RAP), and mapping RNA genome interactions (MARGI)
four techniques developed to map the genomic binding sites of RNA. They are often used to discover the roles and mechanisms of lncRNAs on chromatin.
Nuclear speckle
Speckles are conserved nuclear domains that are present in the form of 10–30 irregularly shaped nuclear structures. Speckles are enriched with RNAs and

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