Trends in Genetics
ReviewNuclear Long Noncoding RNAs: Key Regulators of Gene Expression
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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