BC200 lncRNA

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BC200 RNA BC200 RNA Structure.png
BC200 RNA
BCYRN1
Identifiers
Aliases BCYRN1 , BC200, BC200a, LINC00004, NCRNA00004, brain cytoplasmic RNA 1, BC200 lncRNA
External IDs OMIM: 606089 GeneCards: BCYRN1
Orthologs
SpeciesHumanMouse
Entrez

618

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Ensembl

ENSG00000236824

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UniProt

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a

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC) Chr 2: 47.34 – 47.34 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Brain cytoplasmic 200 long-noncoding RNA (or BC200 lncRNA) is a 200 nucleotide RNA transcript found predominantly in the brain with a primary function of regulating translation by inhibiting its initiation. [3] [4] As a long non-coding RNA, it belongs to a family of RNA transcripts that are not translated into protein (ncRNAs). Of these ncRNAs, lncRNAs are transcripts of 200 nucleotides or longer and are almost three times more prevalent than protein-coding genes. [5] Nevertheless, only a few of the almost 60,000 lncRNAs have been characterized, and little is known about their diverse functions (transcriptional interference, chromatin remodeling, splicing, translation regulation, interaction with miRNAs and siRNAs, and mRNA degradation). [6] [5] BC200 is one lncRNA that has given insight into their specific role in translation regulation, and implications in various forms of cancer as well as Alzheimer's disease.

Contents

The accepted gene symbol for the BC200-coding gene is BCYRN1, for Brain cytoplasmic RNA 1. [7]

Characteristics

A repeat polymorphism of cytosines and adenines (CA) was found to be near BCYRN1 and was used as a reference for mapping the gene. [8] Linkage mapping and radiation hybrid mapping localized the BCYRN1 gene to chromosome 2p16. [8]

As a long non-coding cytoplasmic RNA, BC200 RNA is a part of the largest group of non-coding transcripts in the human genome, which is more prevalent than protein coding genes. The 5' region (left arm) of monomeric Alu short interspersed repetitive elements (SINEs) allows for BC200 RNA transposition and has been evolutionarily conserved in other primates. [9] Of this group of SINEs, BC200 is one of few that are transcriptionally active. In humans, it is found in neuropil areas which are composed of predominantly unmyelinated dendrites, axons, and glial cells. [10]

Similarly, the functional analog of BC200 RNA in rodents (BC1 RNA) is expressed largely in somatodendritic domains of the nervous system, making it an ideal model for experimentation. One large difference is in origin; BC200 emerged from retrotransposed Alu domain, while BC1 originated from retrotransposed tRNA Ala. [11] Although they evolved separately, both are not usually expressed in non-neural somatic cells, with the exception of tumors. [12]

Structure

The BC200 RNA is the product of an unprocessed monomeric Alu sequence. It is 200 nucleotides long and non-translatable.

BC200 has three distinct structural domains. The 5' region of the RNA defines one domain and consists of Alu repeat elements. The other two structural domains are a central A-rich region, and a C-rich 3' region specific to BC200. [3] The 5' end of this molecule has both primary and secondary structure that is very similar to 7SL RNA, a signal recognition particle RNA (SRP) which also includes a 5' Alu domain. [13]

The BC200 RNA gene has two pseudogenes: BC200 beta and BC200 gamma. These two pseudogenes each have a single gene in the genome, located on separate chromosomes. The beta pseudogene is composed of a BC200 RNA gene and additional Alu sequences. The gamma pseudogene contains an inverted long interspersed nuclear element (LINE). They both have transpositional ability, but the exact mechanism is unknown. [12]

Biosynthesis

BC200 RNA Biosynthesis BC200 RNA.png
BC200 RNA Biosynthesis

The biosynthesis of BC200 RNA occurs at the cell body of a neuron and requires upstream promoter elements, downstream internal promoter elements (intragenic A and B boxes), at least two transcription factor binding sites, a TATA-like sequence, TATA-box binding protein (TBP), and RNA polymerase III. [11]

There is a deletion of sequences between -100 and -1 in the DNA that blocks transcription activity, [11] revealing that the transcription complex must interact with this 100-bp sequence of the upstream region for proper synthesis of BC200 RNA. The TATA-box binding protein (TBP) binds here, and when inhibited, BC200 RNA levels decrease, [11] indicating that the 100 base pair region and TBP are critical players in the biosynthesis of BC200 RNA.

In addition to upstream elements, there is an upstream TATGAAA sequence (similar to TATA box sequence) at positions -28 to -22 which, when deleted, compromises transcription, [11] revealing this TATA-like sequence as another critical player in the synthesis of BC200 RNA. However, transcription is not dependent on the TATA-box binding protein binding to the TATA-like sequence. [11]

Both upstream and internal promoter elements are also essential for BC200 RNA synthesis. There are two types of upstream promoter elements in the 100 base pair region: one proximal to the transcription start site and associated with downstream transcription factor binding sites, and the other between nucleotides -36 and -100 and not associated with downstream binding sites. [11] The internal promoter elements are intragenic A and B boxes with A located at position +5 to +15 and B located at position +78 to +88. Any mutation in these boxes can result in a decrease of BC200 RNA. [11]

Because BC200 RNA acts as a translational regulator, it is then transported to the dendrites to bind to specific proteins involved in translation and inhibit their activity (see next section). [11]

Function

BC200 RNA is expressed in the dendrites as ribonucleoprotein particles. Protein synthesis at the synapses of neurons contribute to neuronal plasticity and help prevent neuronal degradation. Small, non-coding RNAs such as BC200 RNA work to repress translation by inhibiting its initiation. During eukaryotic translation, the preinitiation complex binds mRNA and scans the coding strand for a start codon. This step is often subject to the control of a family of initiation factors and these factors are often a target for translational regulators. Poly(A)-binding protein (PABP) has been shown to bind to BC200 RNA further confirming their role as regulators of protein biosynthesis in synapses. [14]

BC200 RNA targets an ATP-dependent RNA helicase called eukaryotic initiation factor 4A (eIF4A). eIF4A requires energy from ATP hydrolysis to unwind the double helix and initiate translation. However, BC200 RNA interferes with the transmission of energy after hydrolysis by changing the conformation of eIF4A, and thus the energy needed to unwind the double helix is never appropriately supplied and initiation of translation is inhibited. [4]

This highly localized uncoupling of the ATPase activity, and subsequently the unwinding of the RNA duplex is proposed to have evolved as a result of the growing complexity of postsynaptic neurons and neuronal activities. Non-coding RNA molecules evolve at a much faster rate than gene-encoding proteins; thus, the sustained conservation of the BC200 RNA transcript indicates its importance for nervous system function. [4]

Applications and role in disease

Cancer

BC200 RNA has been found to be a factor in numerous types of cancer. Although this type of RNA is normally expressed in neurons, it has been detected in cancers of the breast, cervix, esophagus, lungs, ovaries, parotid glands, tongue, and the colon. [15] In certain cancers, expression of BC200 RNA is upregulated. This occurs in esophageal squamous cell carcinoma (ESCC) and higher expression is considered to be a predictor of poor prognosis and may serve as a predictive biomarker for the disease. [16] It was also discovered to be overexpressed in tumor cells of colorectal cancer where the transcript is located just next to a known oncogene, epithelial cell adhesion molecule (EpCAM). [15] Here, expression of BC200 RNA and EpCAM are believed to be correlated as they both play a role in cell migration and invasion. [15] Conversely, research has indicated that BC200 RNA is downregulated in ovarian cancer, as it is a tumor suppressor in normal ovarian cells controlling proliferative ability. [17]

Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease resulting from synaptic plasticity failure. BC200 RNA plays a role in the dendrites of neurons thought to modulate synthesis of proteins that influence this plasticity. [10] Researchers posit that upregulation of BC200 RNA results in an inadequate delivery of RNA to the neuronal synapses, thus resulting in neurodegeneration. [10] In comparing healthy brains with those with AD, it was determined that BC200 RNA is upregulated in the brains of people with AD, most notably in areas of the brain that correspond to the disease. [10] A direct relationship was observed here, the more severe the disease, the higher the levels of BC200 RNA there were. [10] This is in contrast to a normal aging brain where a steady decrease of this RNA is observed between the ages of 49 and 86. [10]

Potential target

LncRNA has evolved rather recently from those of other species but still maintains some functionality. [18] With regards to this specific form, researchers believe that it can serve as a diagnostic and predictive biomarker for cancers where its normal expression is altered. [15] Much work is still required to fully understand the function and regulatory mechanisms of BC200 RNA but new approaches may seek to develop probes for human BC200 RNA that will assist in developing novel pharmaceuticals. [19] As RNA polymerase III is responsible for transcribing BC200 RNA, it can also serve as a potential target for addressing disease where the expression of it is elevated. [18]

Related Research Articles

<span class="mw-page-title-main">Promoter (genetics)</span> Region of DNA encouraging transcription

In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of itself, such as tRNA or rRNA. Promoters are located near the transcription start sites of genes, upstream on the DNA . Promoters can be about 100–1000 base pairs long, the sequence of which is highly dependent on the gene and product of transcription, type or class of RNA polymerase recruited to the site, and species of organism.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called non-coding RNAs (ncRNAs). mRNA comprises only 1–3% of total RNA samples. Less than 2% of the human genome can be transcribed into mRNA, while at least 80% of mammalian genomic DNA can be actively transcribed, with the majority of this 80% considered to be ncRNA.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

<span class="mw-page-title-main">Three prime untranslated region</span> Sequence at the 3 end of messenger RNA that does not code for product

In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally influence gene expression.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

In molecular biology, the TATA box is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a shorter consensus sequence.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

<span class="mw-page-title-main">Retrotransposon</span> Type of genetic component

Retrotransposons are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through the reverse transcription process using an RNA transposition intermediate.

Immediate early genes (IEGs) are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized. IEGs are distinct from "late response" genes, which can only be activated later, following the synthesis of early response gene products. Thus IEGs have been called the "gateway to the genomic response". The term can describe viral regulatory proteins that are synthesized following viral infection of a host cell, or cellular proteins that are made immediately following stimulation of a resting cell by extracellular signals.

<span class="mw-page-title-main">L1 (protein)</span> Mammalian protein found in Homo sapiens

L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.

RNA-binding proteins are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif (RRM), dsRNA binding domain, zinc finger and others. They are cytoplasmic and nuclear proteins. However, since most mature RNA is exported from the nucleus relatively quickly, most RBPs in the nucleus exist as complexes of protein and pre-mRNA called heterogeneous ribonucleoprotein particles (hnRNPs). RBPs have crucial roles in various cellular processes such as: cellular function, transport and localization. They especially play a major role in post-transcriptional control of RNAs, such as: splicing, polyadenylation, mRNA stabilization, mRNA localization and translation. Eukaryotic cells express diverse RBPs with unique RNA-binding activity and protein–protein interaction. According to the Eukaryotic RBP Database (EuRBPDB), there are 2961 genes encoding RBPs in humans. During evolution, the diversity of RBPs greatly increased with the increase in the number of introns. Diversity enabled eukaryotic cells to utilize RNA exons in various arrangements, giving rise to a unique RNP (ribonucleoprotein) for each RNA. Although RBPs have a crucial role in post-transcriptional regulation in gene expression, relatively few RBPs have been studied systematically.It has now become clear that RNA–RBP interactions play important roles in many biological processes among organisms.

<span class="mw-page-title-main">Silencer (genetics)</span> Type of DNA sequence

In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.

The cytoplasmic polyadenylation element (CPE) is a sequence element found in the 3' untranslated region of messenger RNA. While several sequence elements are known to regulate cytoplasmic polyadenylation, CPE is the best characterized. The most common CPE sequence is UUUUAU, though there are other variations. Binding of CPE binding protein to this region promotes the extension of the existing polyadenine tail and, in general, activation of the mRNA for protein translation. This elongation occurs after the mRNA has been exported from the nucleus to the cytoplasm. A longer poly(A) tail attracts more cytoplasmic polyadenine binding proteins (PABPs) which interact with several other cytoplasmic proteins that encourage the mRNA and the ribosome to associate. The lengthening of the poly(A) tail thus has a role in increasing translational efficiency of the mRNA. The polyadenine tails are extended from approximately 40 bases to 150 bases.

<span class="mw-page-title-main">PURA</span> Protein-coding gene in the species Homo sapiens

Pur-alpha is a protein that in humans is encoded by the PURA gene located at chromosome 5, band q31.

<span class="mw-page-title-main">RE1-silencing transcription factor</span> Protein-coding gene in the species Homo sapiens

RE1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a protein which in humans is encoded by the REST gene, and acts as a transcriptional repressor. REST is expressly involved in the repression of neural genes in non-neuronal cells. Many genetic disorders have been tied to alterations in the REST expression pattern, including colon and small-cell lung carcinomas found with truncated versions of REST. In addition to these cancers, defects in REST have also been attributed a role in Huntington Disease, neuroblastomas, and the effects of epileptic seizures and ischemia.

<span class="mw-page-title-main">STAU1</span> Protein-coding gene in the species Homo sapiens

Double-stranded RNA-binding protein Staufen homolog 1 is a protein that in humans is encoded by the STAU1 gene.

<span class="mw-page-title-main">Long non-coding RNA</span> Non-protein coding transcripts longer than 200 nucleotides

Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.

<span class="mw-page-title-main">Circular RNA</span> Type of RNA found in cells

Circular RNA is a type of single-stranded RNA which, unlike linear RNA, forms a covalently closed continuous loop. In circular RNA, the 3' and 5' ends normally present in an RNA molecule have been joined together. This feature confers numerous properties to circular RNA, many of which have only recently been identified.

Epigenetics of human development is the study of how epigenetics effects human development.

<span class="mw-page-title-main">Jürgen Brosius</span> German molecular geneticist and evolutionary biologist

Jürgen Brosius in Saarbrücken) is a German molecular geneticist and evolutionary biologist. He was professor and director of the Institute of Experimental Pathology at the University of Münster. Some of his scientific contributions involve the first genetic sequencing of a ribosomal RNA operon, the design of plasmids for studying gene expression, expression vectors for high-level production of recombinant proteins and RNA, RNA biology, RNomics as well as the significance of retroposition for plasticity and evolution of genomes, genes and gene modules including regulatory sequences or elements.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000236824 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 Tiedge, Henri; Chen, Wei; Brosius, Jürgen (1 June 1993). "Primary Structure, Neural-Specific Expression, and Dendritic Location of Human BC200 RNA". Journal of Neuroscience. 13 (6): 2382–2390. doi:10.1523/JNEUROSCI.13-06-02382.1993. PMC   6576500 . PMID   7684772.
  4. 1 2 3 Lin, Daisy; et al. (May 2008). "Translational Control by a Small RNA: Dendritic BC1 RNA Targets the Eukaryotic Initiation Factor 4A Helicase Mechanism". Molecular and Cellular Biology. 28 (9): 3008–3019. doi:10.1128/MCB.01800-07. PMC   2293081 . PMID   18316401.
  5. 1 2 Bhadra, Utpal; Chowdhury, Debabani Roy; Mondal, Tanmoy; Bhadra, Manika Pal (2016). "Long Noncoding RNAs are Frontier Breakthrough of RNA World and RNAi-based Gene Regulation". RNA Interference. INTECH. pp. 63–86.
  6. ↑ Ma, Lina; Bajic, Vladimir B.; Zhang, Zhang (April 15, 2013). "On the classification of long non-coding RNAs". RNA Biol. 6 (10): 924–933. doi:10.4161/rna.24604. PMC   4111732 . PMID   23696037.
  7. ↑ "Entrez Gene: Brain cytoplasmic RNA 1" . Retrieved 2017-10-08.
  8. 1 2 Basile, V; Vicente, A; Martignetti, J. A.; Skyrabin, B. V.; Brosius, J; Kennedy, J. L. (February 1998). "Assignment of the human BC200 RNA gene (BCYRN1) to chromosome 2p16 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 82 (3–4): 271–272. doi:10.1159/000015117. PMID   9858834. S2CID   84998889 . Retrieved 10 October 2017.
  9. ↑ B.V. Skryabin, J; Kremerskothen, D; Vassilacopoulou, T. R.; Disotell, V.V. (December 1998). "The BC200 RNA gene and its neural expression are conserved in Anthropoidea (Primates)". J Mol Evol. 47 (6): 677–685. Bibcode:1998JMolE..47..677S. doi:10.1007/PL00006426. PMID   9847409. S2CID   194302.
  10. 1 2 3 4 5 6 Mus, El; Hof, Patrick R.; Tiedge, Henri (6 June 2007). "Dendritic BC200 RNA in aging and in Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America. 104 (25): 10679–10684. Bibcode:2007PNAS..10410679M. doi: 10.1073/pnas.0701532104 . PMC   1965572 . PMID   17553964.
  11. 1 2 3 4 5 6 7 8 9 Kim, Youngmi; et al. (31 July 2017). "Biosynthesis of Brain Cytoplasmic 200 RNA". Scientific Reports. 7 (1): 6884. Bibcode:2017NatSR...7.6884K. doi:10.1038/s41598-017-05097-3. PMC   5537265 . PMID   28761139.
  12. 1 2 Martignetti, J; Brosius, J (15 December 1993). "BC200 RNA: a Neural RNA Polymerase III Product Encoded by a Monomeric Alu Element". Proceedings of the National Academy of Sciences of the United States of America. 90 (24): 11563–11567. Bibcode:1993PNAS...9011563M. doi: 10.1073/pnas.90.24.11563 . PMC   48024 . PMID   8265590.
  13. ↑ Kremerskothen, J.; Zopf, D.; Walter, P.; Cheng, J. G.; Nettermann, M.; Niewerth, U.; Maraia, R. J.; Brosius, J. (1998-04-10). "Heterodimer SRP9/14 is an integral part of the neural BC200 RNP in primate brain". Neuroscience Letters. 245 (3): 123–126. doi:10.1016/S0304-3940(98)00215-8. ISSN   0304-3940. PMID   9605471. S2CID   16565899.
  14. ↑ Muddashetty, Ravi; Khanam, Tasneem; Kondrashov, Alexander; Bundman, Marsha; Iacoangeli, Anna; Kremerskothen, Joachim; Duning, Kerstin; Barnekow, Angelika; Hüttenhofer, Alexander (2002-08-16). "Poly(A)-binding protein is associated with neuronal BC1 and BC200 ribonucleoprotein particles". Journal of Molecular Biology. 321 (3): 433–445. CiteSeerX   10.1.1.328.1975 . doi:10.1016/S0022-2836(02)00655-1. ISSN   0022-2836. PMID   12162957.
  15. 1 2 3 4 Li, Peng; Yang, Bo; Xia, Shaoyou; Chen, Li; Ning, Ning (15 February 2016). "BC200 RNA is over-expressed in colorectal cancer and promotes migration and invasion of HCT116 cells" (PDF). International Journal of Clinical and Experimental Pathology. pp. 1481–1486. Retrieved 10 October 2017.
  16. ↑ Zhao, Rui-Hua; Zhu, Cai-hua; Li, Xiang-Ki; Cao, Wei; Zong, Hong (15 April 2016). "BC200 LncRNA a potential predictive marker of poor prognosis in esophageal squamous cell carcinoma patients". OncoTargets and Therapy. 9: 2221–2226. doi: 10.2147/OTT.S99401 . PMC   4846077 . PMID   27143917.
  17. ↑ Wu, Di; Wang, Tianzhen; Ren, Chengcheng; Liu, Lei; Kong, Dan (1 December 2015). "Downregulation of BC200 in ovarian cancer contributes to cancer cell proliferation and chemoresistance to carboplatin". Oncology Letters. 11 (2): 1189–1194. doi:10.3892/ol.2015.3983. PMC   4734031 . PMID   26893717.
  18. 1 2 Prabhakar, Bindu; Zhong, Xiao-bo; Rasmussen, Theodore P. (29 March 2017). "Exploiting Long Noncoding RNAs as Pharmacological Targets to Modulate Epigenetic Diseases". The Yale Journal of Biology and Medicine. 90 (1): 73–86. PMC   5369047 . PMID   28356895.
  19. ↑ Wahlestedt, Claes (31 May 2013). "Targeting long non-coding RNA to therapeutically upregulate gene expression". Nature Reviews Drug Discovery. 12 (6): 433–436. doi:10.1038/nrd4018. PMID   23722346. S2CID   288163.

Further reading

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