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LncRNA Research

LncRNA: Why and How to Study it?

 

Introduction

Long non-coding RNAs (LncRNAs) are evolutionarily conserved, longer than 200nt, non-coding RNA molecules found in eukaryotes. Growing evidence suggests that LncRNAs have emerged as important regulators for diverse functions1.  LncRNAs are involved in a surprisingly wide variety of cellular functions, including epigenetic silencing, transcriptional regulation, RNA processing, and RNA modification2.  In addition,  LncRNAs have been associated with human diseases such as cancers, Alzheimer's disease, and heart diseases3.  Having a better understanding of LncRNA's functional roles has tremendous potential to advance our understanding of cell regulatory and disease mechanisms.

What are Long non-coding RNAs?

Abundance of LncRNA

The majority of genomes are transcribed to produce LncRNAs. LncRNA's expression is under precise control at all levels during gene expression and processing. LncRNAs are expressed at low levels and can be found in many specific tissue types, subcellular compartments, or under exact conditions, which raised the challenge to delineate the mechanisms underlying their transcription, regulation, and potential functional roles4.

Genomic Organization

 It is becoming evident that the vast majorities of non-coding RNAs overlap with, or are transcribed antisense to, protein-coding genes or are expressed as intergenic or intronic regions of the genome.

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Figure.1 Genomic relationship between LncRNA and protein coding genes.

Evolution and Conservation

 In contrast to microRNAs, LncRNAs generally lack strong conservation. Many well-described LncRNAs, such as Air and Xist, are poorly conserved.  LncRNAs sequence may be more plastic than protein coding genes and thus can evolve rapidly. However, LncRNA promoter sequences are often very well conserved5. More recently it has been reported that some large intergenic non-coding RNAs (lincRNAs) are enriched in evolutionarily conserved sequences 6.

Cellular Localization

 The tissue-specific expression patterns of many LncRNAs seen in development, and the distinct subcellular localization of lncRNAs, strongly suggest that their expression is under precise control. Although some LncRNAs have been reported to be transcribed by RNA polymerase III, the majority are transcribed by RNA polymerase II. In contrast to most mRNAs, which ultimately localize to the cytoplasm after processing, most LncRNAs are permanently localized in the nucleus7. There are also some LncRNAs selectively localized in the cytoplasm8.

Why Do We Study LncRNAs?

Recent findings suggest that LncRNAs function in various aspects of cell biology has increased awareness for their potential to contribute towards disease. Many association studies have identified LncRNAs that are aberrantly expressed in disease states, especially cancer.

Linking LncRNA and Cancer

The over-expression of some specific LncRNAs has also been found to be a good marker for several tumors. Colon carcinoma cells show significantly higher levels of OCC-1 gene transcripts9. In prostatic tumors, two LncRNA genes, PCA3 and PCGEM1, are significantly over-expressed compared with normal tissue10.  The expression of the LncRNA MALAT1 correlates with tumor development, progression or survival in lung, liver and breast cancer11. More recently, the highly conserved mouse homologue of MALAT1 was found to be highly expressed in hepatocellular carcinoma12. The LncRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of PRC2 to an occupancy pattern13. Learn more >>

LncRNA and Other Diseases

In addition to cancer, LncRNAs also exhibit aberrant expression in other disease states, such as heart diseases, psoriasis and Alzheimer's disease. Recently, it has been demonstrated that over-expression of a LncRNA, PRINS is associated with psoriasis susceptibility14. An antisense LncRNA, BACEAS, that regulates the expression of the sense BACE1 gene, a crucial enzyme in Alzheimer's disease etiology, exhibits elevated expression in several regions of the brain in individuals with Alzheimer's disease. Alteration of the expression for LncRNAs may also mediate changes at an epigenetic level to effect gene expression and contribute to disease etiology, suggesting that this LncRNA may serve as an attractive drug target candidate for Alzheimer's disease15Learn more >>

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Figure.2 BACEAS promote Alzheimer's disease progression.

How to Study LncRNAs?

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Figure.3 How to Study LncRNAs

Related Services
LncRNA Array Service
LncPath™ Array Service
T-UCR Array Service

References1.    Mercer, T.R., Dinger, M.E. & Mattick, J.S. Long non-coding RNAs: insights into functions. Nat Rev Genet 10, 155-9 (2009).
2.    Amaral, P.P., Dinger, M.E., Mercer, T.R. & Mattick, J.S. The eukaryotic genome as an RNA machine. Science 319, 1787-9 (2008).
3.    Taft, R.J., Pang, K.C., Mercer, T.R., Dinger, M. & Mattick, J.S. Non-coding RNAs: regulators of disease. J Pathol 220, 126-39.
4.    Wang, X., Song, X., Glass, C.K. & Rosenfeld, M.G. The Long Arm of Long Noncoding RNAs: Roles as Sensors Regulating Gene Transcriptional Programs. Cold Spring Harb Perspect Biol.
5.    Ponting, C.P., Oliver, P.L. & Reik, W. Evolution and functions of long noncoding RNAs. Cell 136, 629-41 (2009).
6.    Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223-7 (2009).
7.    Kapranov, P. et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316, 1484-8 (2007).
8.    Louro, R., Smirnova, A.S. & Verjovski-Almeida, S. Long intronic noncoding RNA transcription: expression noise or expression choice? Genomics 93, 291-8 (2009).
9.    Pibouin, L. et al. Cloning of the mRNA of overexpression in colon carcinoma-1: a sequence overexpressed in a subset of colon carcinomas. Cancer Genet Cytogenet 133, 55-60 (2002).
10.  Fu, X., Ravindranath, L., Tran, N., Petrovics, G. & Srivastava, S. Regulation of apoptosis by a prostate-specific and prostate cancer-associated noncoding gene, PCGEM1. DNA Cell Biol 25, 135-41 (2006).
11.   Tripathi, V. et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39, 925-38.
12.   Lin, R., Maeda, S., Liu, C., Karin, M. & Edgington, T.S. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26, 851-8 (2007).
13.   Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071-6.
14.   Sonkoly, E. et al. Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS. J Biol Chem 280, 24159-67 (2005).
15.    Faghihi, M.A. et al. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med 14, 723-30 (2008).

 

 

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