![BC200 RNA Structure](https://upload.wikimedia.org/wikipedia/commons/1/13/BC200_RNA_Structure.png)
Brain cytoplasmic 200 long-noncoding RNA (or BC200 lncRNA) is a 200 nucleotide
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
transcript found predominantly in the brain with a primary function of regulating
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
by inhibiting its initiation.
As a
long non-coding RNA
Long non-coding RNAs (long ncRNAs, lncRNA) 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 mic ...
, 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.
Nevertheless, only a few of the almost 60,000 lncRNAs have been characterized, and little is known about their diverse functions (
transcriptional
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 calle ...
interference,
chromatin remodeling
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
,
splicing, translation regulation, interaction with
miRNAs
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miR ...
and
siRNA
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...
s, and mRNA degradation).
BC200 is one lncRNA that has given insight into their specific role in translation regulation, and implications in various forms of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
as well as
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
.
The accepted
gene symbol
Gene nomenclature is the scientific naming of genes, the units of heredity in living organisms. It is also closely associated with protein nomenclature, as genes and the proteins they code for usually have similar nomenclature. An international co ...
for the BC200-coding gene is BCYRN1, for Brain cytoplasmic RNA 1.
[
]
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.
Linkage mapping and
radiation hybrid mapping localized the BCYRN1 gene to chromosome 2p16.
As a long non-coding cytoplasmic RNA, BC200 RNA is a part of the largest group of non-coding transcripts in the
human genome
The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the n ...
, which is more prevalent than protein coding
genes
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. The 5' region (left arm) of monomeric
Alu short interspersed repetitive elements (
SINEs
Sines () is a city and a municipality in Portugal. The municipality, divided into two parishes, has around 14,214 inhabitants (2021) in an area of . Sines holds an important oil refinery and several petrochemical industries. It is also a popular ...
) allows for BC200 RNA transposition and has been evolutionarily conserved in other primates.
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
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, th ...
, and
glial cells
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...
.
Similarly, the functional analog of BC200 RNA in rodents (BC1 RNA) is expressed largely in
somatodendritic
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
domains of the
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
, 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
Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...
Ala.
Although they evolved separately, both are not usually expressed in non-neural
somatic cells
A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Such cells compo ...
, with the exception of
tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
.
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.
The 5' end of this molecule has both primary and secondary structure that is very similar to 7SL RNA, a
signal recognition particle RNA
The signal recognition particle RNA, (also known as 7SL, 6S or 4.5S RNA) is part of the signal recognition particle (SRP) ribonucleoprotein complex. SRP recognizes the signal peptide and binds to the ribosome, halting protein synthesis. Signal re ...
(SRP) which also includes a 5' Alu domain.
The BC200 RNA gene has two
pseudogenes
Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are ...
: BC200 beta and BC200 gamma. These two pseudogenes each have a single gene in the genome, located on separate
chromosomes
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
. 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.
Biosynthesis
![BC200 RNA](https://upload.wikimedia.org/wikipedia/commons/b/b0/BC200_RNA.png)
The biosynthesis of BC200 RNA occurs at the cell body of a
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
and requires
upstream promoter elements, downstream internal promoter elements (intragenic A and B boxes), at least two
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
binding sites, a TATA-like sequence,
TATA-box
In molecular biology, the TATA box (also called the Goldberg–Hogness 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 ha ...
binding protein (TBP), and
RNA polymerase III
In eukaryote cells, RNA polymerase III (also called Pol III) is a protein that transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs.
The genes transcribed by RNA Pol III fall in the category of "housekeeping" genes whose e ...
.
There is a deletion of sequences between -100 to -1 in the DNA that blocks transcription activity,
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,
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,
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.
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 to -100 and not associated with downstream binding sites.
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.
Because BC200 RNA acts as a translational regulator, it is then transported to the
dendrites
Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the n ...
to bind to specific proteins involved in translation and inhibit their activity (see next section).
Function
BC200 RNA is expressed in the dendrites as
ribonucleoprotein particle
A ribonucleoprotein particle or RNP is vessicle complex formed between RNA and RNA-binding proteins (RBPs). The term RNP foci can also be used to denote intracellular compartments involved in processing of RNA transcripts.
RNA/RBP complexes
R ...
s. Protein synthesis at the
synapses
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
of neurons contribute to
neuronal plasticity
Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it p ...
and help prevent neuronal degradation. Small, non-coding RNAs such as BC200 RNA work to repress translation by inhibiting its initiation. During
eukaryotic translation
Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: gene translation, elongation, termination, and recapping.
Initiation
Translation initiation is the pr ...
, the preinitiation complex binds
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
and scans the coding strand for a
start codon
The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and Archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids. The ...
. This step is often subject to the control of a family of
initiation factors Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.
Initiation factors can interact with repressors to slow down or prevent translation. They have the ...
and these factors are often a target for translational regulators.
Poly(A)-binding protein
Poly(A)-binding protein (PAB or PABP) is an RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on the ...
(PABP) has been shown to bind to BC200 RNA further confirming their role as regulators of protein biosynthesis in synapses.
BC200 RNA targets an ATP-dependent RNA
helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...
called eukaryotic initiation factor 4A (
eIF4A
The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that f ...
). eIF4A requires energy from
ATP hydrolysis
ATP hydrolysis is the catabolic reaction process by which chemical energy that has been stored in the high-energy phosphoanhydride bonds in adenosine triphosphate (ATP) is released after splitting these bonds, for example in muscles, by prod ...
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.
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.
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
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and secret ...
,
cervix
The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...
,
esophagus
The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...
,
lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...
,
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
,
parotid glands
The parotid gland is a major salivary gland in many animals. In humans, the two parotid glands are present on either side of the mouth and in front of both ears. They are the largest of the salivary glands. Each parotid is wrapped around the ma ...
,
tongue
The tongue is a muscular organ (anatomy), organ in the mouth of a typical tetrapod. It manipulates food for mastication and swallowing as part of the digestive system, digestive process, and is the primary organ of taste. The tongue's upper surfa ...
, and the
colon.
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.
It was also discovered to be overexpressed in tumor cells of colorectal cancer where the transcript is located just next to a known
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , epithelial cell adhesion molecule (
EpCAM
Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, prol ...
).
Here, expression of BC200 RNA and EpCAM are believed to be correlated as they both play a role in cell migration and invasion.
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.
Alzheimer's disease
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(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.
Researchers posit that upregulation of BC200 RNA results in an inadequate delivery of RNA to the neuronal synapses, thus resulting in
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
.
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.
A direct relationship was observed here, the more severe the disease, the higher the levels of BC200 RNA there were.
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.
Potential target
LncRNA has evolved rather recently from those of other species but still maintains some functionality.
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.
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.
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.
References
Further reading
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External links
"BRAIN CYTOPLASMIC RNA 1; BCYRN1.""Alu elements: know the SINEs""The Long Non-Coding RNA BC200 (BCYRN1) Is Critical for Cancer Cell Survival and Proliferation.""Expression of neural BC200 RNA in human tumours.""Knockdown of BC200 RNA expression reduces cell migration and invasion by destabilizing mRNA for calcium-binding protein S100A11."{{NLM content
Non-coding RNA
Neurochemistry