This document discusses long non-coding RNAs (lncRNAs), which are RNA molecules longer than 200 nucleotides that do not code for proteins but play important regulatory roles. It describes the central dogma of molecular biology and how most of the human genome is transcribed into non-coding RNA. It classifies lncRNAs and explains their potential functions as signals, decoys, guides and scaffolds. The document also discusses the roles of lncRNAs in several human diseases like cancer, Alzheimer's, diabetes and more. It concludes that lncRNAs are important biomarkers and therapeutic targets due to their involvement in complex disease pathogenesis.
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lncRNA Role in Disease Pathogenesis and Clinical Applications
1. lncRNA AND THEIR CLINICAL PERSPECTIVE
PRESENTED BY
MOHIT
REG.NO.- mslsmm01
M.Sc 2ND Sem. (CREDIT SEMINAR)
CENTER OF HUMAN GENETICS AND MOLECULAR MEDICINE
SCHOOL OF HEALTH SCIENCES
CENTRAL UNIVERSITY OF PUNJAB, BATHINDA
2. Central Dogma of Molecular Biology
“The central dogma of molecular biology
deals with the detailed residue-by-residue
transfer of sequential information. It states
that such information cannot be
transferred back from protein to either
protein or nucleic acid.”
-Francis Crick, 1958
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3. … in other words
Protein information
cannot flow back to
nucleic acids
Fundamental
framework to
understanding the
transfer of sequence
information between
biopolymers
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4. 4/2/2016 8:03 AM 4
.
FACTS:
• Less than 2% of the human genome encodes
proteins
•The bulk of transcriptional products consists of small
and long RNAs with very reduced coding potential
most eukaryotic transcribed DNA is non-coding
• C-value paradox
genome size does
not correlate with
organismal
complexity
• Gene-value
paradox;
relationship between
morphological
complexity and the
number of protein-
coding genes within
a genome
• simplistic
expectation +
contradictory data
= “paradox”
• The number of human genes is about the same as the
number required to specify a C. elegans
• The secret of evolution lies in gene regulation
complexity?
Prevasive Genome Transcription
5. • Main observations:
• Intronic transcripts
• Intergenic RNAs
• Antisense and overlapping transcription
• Concept of “transcribed dark matter”, i.e. transcripts with
unknown function and meaning
• Tests of function that depend on gene knockout or overexpression
only work for a fraction even of known protein-coding genes. Need to
establish non coding transcripts function
Prevasive Genome Transcription
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6. • RNA molecules both encode sequence information and possess great structural
plasticity
• RNA can directly interact with DNA and with other RNAs by base pairing
• Highly structured RNA can also provide docking sites for binding proteins
• RNA has a compact size and significant sequence specificity
• non-coding RNA known from long time:
• rRNA and tRNA in translation
• snRNA and snoRNA in mRNA processing
• ribozymes
Non-coding RNA
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7. • Genome-wide surveys have revealed that eukaryotic genomes are extensively
transcribed into thousands of long and short ncRNAs
• Important small ncRNA with regulatory roles:
• miRNAs
• siRNAs
• piRNAs (Piwi-interacting RNA, transposon silencing in spermatogenesis)
• Long ncRNAs, lncRNAs >200 nt
• Many lncRNAs show spatial and specific patterns of expression, indicating that
lncRNA expression is strongly regulated
• lncRNAs have specific biological functions
SMALL AND LONG NON-CODING RNA
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8. Characteristic's Of lncRNAs
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8
lncRNAs are
3' polyadenylated,
5' capped,
multi-exonic
transcriptional activation
Splicing activity.
mostly transcribed RNA polymerase II
They do not undergo, the standard mRNA processing .
lncRNA promoters are bound and regulated by transcriptional factors, including
Oct3/4, Sp1, Sox2, and p53.
No obvious ORF
80% of the transcription in mammalian genomes is exclusively associated with
long non-coding RNAs (lncRNAs)
11. long non-coding
RNA sare
transcribed from
introns of the
protein-coding
region in
different
GENOMIC
location in
Human genome
Intronic lncRNA
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Source :- (Ma et al., 2013)
13. These are transcribed
from sense strand of
protein-coding genes,
containing exon from
the mRNA that
containing protein
coding gene. It may
cover or overlap the
whole protein coding
region
Sense lncRNAs
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Source :- (Ma et al., 2013)
15. lncRNA Mechanisms can be described according to four, not mutually exclusive, archetypes:
• As signals
• As decoys
• As guides
• As scaffolds
lncRNAs Molecular Mechanisms
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16. lncRNAs can serve as molecular signals, because
transcription of individual lncRNAs occurs at a very specific
time and place to integrate developmental cues, interpret
cellular context, or respond to diverse stimuli.
the lncRNAs in this archetype can act as markers of functionally
significant biological events.
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Source :- (Wang and Chang, 2011)
e.g. Pluripotency and Reprogramming: ROR lncRNA
Pluripotency incorporated lincRNA was initially discovered in ESCs of a mouse.
Somatic cell reprogramming to iPSCs is accompanied by enriched expression of
lincRNAs
lincRNA-RoR, was shown to be directly targeted by the key pluripotency factors
Oct4, Sox2, and Nanog through co-localization of the three factors close its
promoter region
RoR was downregulated upon Oct4 depletion, as well as during differentiation of
iPSCs, implicating co-regulation of specific lincRNAs by key pluripotency factors
lncRNAs As Signals
17. as decoys, The archetype of lncRNAs is
transcribed and then binds and titrates
away a protein target, but does not exert
any additional functions.
probably act by effector negatively
regulating
as decoys, lncRNAs can compete
with mRNAs for miRNA target sites
lncRNAs As Decoys
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17
Source :- (Wang and Chang, 2011)
Glucocorticoid Resistance:-
GAS5 lncRNA make a hairpin loop like structure which make a motif which
similar to DNA motif of that promoter region so it can compete for hormone
to bind as they can act as molecular decoy.
18. • lncRNA is the guide—RNA binds protein(s), then directs the
localization of ribonucleoprotein complex to specific targets.
• lncRNAs can guide changes in gene expression either in
cis (on neighboring genes) or in trans (distantly located
genes) in a manner that is not easily predicted based on
lncRNA sequence.
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Source :- (Wang and Chang, 2011)
The gene regulatory components brought on by the lncRNAs include both
repressive (e.g., polycomb) and activating (MLL) complexes, as well as
transcription factors (TFIIB). However, no matter the distance or mechanism
(either cis or trans), the principle remains the same: to convey regulatory
information across an intervening stretch of DNA to control target gene
expression, bringing about changes in the epigenome.
lncRNAs As Guides
19. lncRNAs As Scaffolds
•They act as scaffolds, lncRNAs can
bring together multiple proteins to form
ribonucleoprotein complexes.
• The lncRNA-RNP may act on
chromatin as to affect histone
modifications.
•LncRNAs can serve as central platforms
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Source :- (Wang and Chang, 2011)
•Telomerase catalytic activity requires the association of two universal telomerase
subunits: an integral RNA subunit, the telomerase RNA (TERC) that provides the
template for repeat synthesis, and a catalytic protein subunit, the TERT, as well as
several species-specific accessory proteins. The TERC in particular also possesses
structures that contribute to TERT binding and catalytic activity, in addition to those that
play major roles in stability of the complex.
• Thus, the primary functional role for TERC is to be a scaffold
26. 4/2/2016 8:03 AM 29
lncRNAs In Diabetes
GWAS studies of type – 2 diabetes and related diseases has revealed >50 susceptibility
loci, most of which are not known to carry variations that alter protein coding sequence.
Such variants affect lncRNAs
There are >1100 intergenic and antisense islet cell lncRNAs found in human islet and beta
cell .
lncRNAs are an integral component of dynamic beta cell-specific differentiation.
HI-LNC25(beta cell specific lncRNA) positively regulates GLIS3 mRNA(encodes an islet
transcription factor)
Mutation in HI-LNC25 cause diabetes.
lncRNAs KCNQ1T1 and HI-LN45 significantly increase or decreased in type -2 diabetes.
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lncRNA are >200nt non-coding RNA, which play important role in gene
expression and its regulation.
lncRNA are classified into 4 types
lncRNA can function as either of the 4 types: as guides, as scaffold, as
signals, as decoys.
These non-coding RNA play significant role in pathogenesis of several
complex diseases.
LncRNA can thus serve as an important biomarker for early detection of
disease, or also can serve as a therapeutic target.
Conclusion
28. Future Prospective:
There is a need for large-scale LOF or gain-of-function studies to
causally demonstrate lncRNA functions..
There is a clear need to develop genetic model systems to understand
lncRNAs’ function in vivo
Use of ASOs, siRNA have been used to target diseases-associated
lncRNAs for therapeutic purpose.
They can act as novel epigenetic intervention tools for specific sites
within the genome
lncRNAs will provide new answer to old questions of evolution and
development
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32
References
Faghihi, M. A., Modarresi, F., Khalil, A. M., Wood, D. E., Sahagan, B. G., Morgan, T. E., ... and Wahlestedt, C.
(2008). Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward
regulation of β-secretase. Nature Medicine, 14(7), 723-730.
Ji, J., Tang, J., Deng, L., Xie, Y., Jiang, R., Li, G., and Sun, B. (2015). LINC00152 promotes proliferation in
hepatocellular carcinoma by targeting EpCAM vis the mTOR signaling pathway. Oncotarget. 32(509).
Li, X., Wu, Z., Fu, X., and Han, W. (2014). lncRNAs: Insights into their function and mechanics in underlying
disorders. Mutation Research/Reviews in Mutation Research, 762, 1-21.
Ma, L., Bajic, V. B., and Zhang, Z. (2013). On the classification of long non-coding RNAs. RNA Biology, 10(6),
924-933. Mercer, T. R., Dinger, M. E., and Mattick, J. S. (2009). Long non-coding RNAs: insights into
functions. Nature Reviews Genetics, 10(3), 155-159.
Ponting, C. P., and Belgard, T. G. (2010). Transcribed dark matter: meaning or myth?. Human Molecular
Genetics, ddq362.
Quinn, J. J., and Chang, H. Y. (2016). Unique features of long non-coding RNA biogenesis and function. Nature
Reviews Genetics, 17(1), 47-62.
Wang, K. C., and Chang, H. Y. (2011). Molecular mechanisms of long noncoding RNAs. Molecular Cell, 43(6),
904-914.V
30. 4/2/2016 8:03 AM 33
Chung, S., Nakagawa, H., Uemura, M., Piao, L., Ashikawa, K., Hosono, N., ... & Tsunoda, T. (2011).
Association of a novel long non‐coding RNA in 8q24 with prostate cancer susceptibility. Cancer
Science, 102(1), 245-252
Zhao, J., Liu, Y., Zhang, W., Zhou, Z., Wu, J., Cui, P., ... & Huang, G. (2015). Long non-coding RNA Linc00152 is
involved in cell cycle arrest, apoptosis, epithelial to mesenchymal transition, cell migration and invasion in
gastric cancer. Cell Cycle, 14(19), 3112-3123.
Zeng, C., Yu, X., Lai, J., Yang, L., Chen, S., and Li, Y. (2015). Overexpression of the long non-coding RNA PVT1 is
correlated with leukemic cell proliferation in acute promyelocytic leukemia. Journal of Hematology and
Oncology, 8(1), 1-6.
Wang, F., Yuan, J. H., Wang, S. B., Yang, F., Yuan, S. X., Ye, C., ... & Sun, S. H. (2014). Oncofetal long noncoding
RNA PVT1 promotes proliferation and stem cell‐like property of hepatocellular carcinoma cells by stabilizing
NOP2. Hepatology, 60(4), 1278-1290.
The expectation that increased developmental complexity
would be reflected in an increased number of protein-coding
genes has not been borne out, and has been termed the
G-value paradox.(
“that the majority of its bases are associated with at least one primary transcript
mall nucleolar ribonucleoproteins (snoRNPs) are widely studied and characterized as guide RNAs for sequence-specific 2′-O-ribose methylation and psuedouridylation of ribosomal RNAs. In addition, snoRNAs have also been shown to interact with some tRNAs and direct alternative splicing in mRNA biogenesis.
small nuclear ribonucleoprotein particles or snRNPs. These snRNPs each seem to have a role in the splicing process. We will talk about just one snRNP, U1.
The function of miRNAs appears to be in gene regulation. For that purpose, a miRNA is complementary to a part of one or more messenger RNAs (mRNAs). Animal miRNAsare usually complementary to a site in the 3' UTR
siRNA is essentially a synthetic, man-made, miRNA molecule, and operates within the RNA interference (RNAi) pathway, where it interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, resulting in no translation.
piRNAs interact with piwi proteins that are part of a family of proteins called the Argonautes. These are active in the testes of mammals and are required for germ-cell and stem-cell development in invertebrates.
Oct-3/4 is a key transcriptional factor whose expression level governs the fate of primitive inner cell mass and embryonic stem (ES) cells.
Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene
The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promoters. The encoded protein is involved in many cellular processes, including cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage, and chromatin remodeling. Post-translational modifications such as phosphorylation, acetylation, glycosylation, and proteolytic processing significantly affect the activity of this protein, which can be an activator or a represso
SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, ...
transformation-related protein 53 (TRP53)
TSS-transcripition start site
Swr1-Th SWR1 complex is involved in chromatin-remodelling by promoting the the ATP-dependent exchange of histone H2A for the H2A variant HZT1 in Saccharomyces cerevisiae (Baker's yeast) or H2AZ in mammals. The SWR1 chromatin-remodelling complex is composed of at least 14 subunits and has a molecular mass of about 1.2 to 1.5 MDa.
In080-The INO80 chromatin remodeling complex functions in transcriptional regulation, DNA repair, and replication. Here we uncover a novel role for INO80 in regulating chromosome segregation.
Rsc-ATP-dependent chromatin-remodeling complexes, such as RSC, can reposition, evict or restructure nucleosomes
Isw2-his system enabled us to analyze the interaction of Isw2 ATP-dependent chromatin remodeling complex with nucleosome nuclear exosome (RNase complex)
Messenger RNAs containing premature stop codons are generally targeted for degradation through the nonsense-mediated mRNA decay (NMD) pathway
small nuclear ribonucleoprotein particles or snRNPs. These snRNPs each seem to have a role in the splicing process. We will talk about just one snRNP, U1.
Myc- can induce global RNA pol II carboxy terminal domain phosphorylation and enhanced
mRNA cap methylation on a subset of mRNA transcriptional elongation (and, to a lesser extent, initi- ation) of
CAF1-chromatin assembly factor – universal repressor of divergent transcription
lincRNA-Regulator of Reprogramming
HOMEOBOX TRANSCRIPTION FACTOR NANOG
Gas5 (Growth arrest specific 5)
Glucocorticoid recepetor involve in metabolism of
When the GR binds to glucocorticoids, its primary mechanism of action is the regulation of gene transcription
Gas5 (Growth arrest specific 5)
Glucocorticoid recepetor involve in metabolism of
When the GR binds to glucocorticoids, its primary mechanism of action is the regulation of gene transcription
TFIIB is phosphorylated at Serine 65 which is found in the B reader domain
MLL complex, a multiprotein complex that mediates both methylation of Lys-4 of histone H3 (H3K4me) complex
POLYCOMB-This complex has histone methyltransferase activity
HOTAIR (for HOX transcript antisense RNA
TLS/FUS (translocated in liposarcoma/fused in sarcoma) regulates target gene transcription via single-stranded DNA response elements
The CREB protein carries out its function by activating transcription, where .... "CBP/p300 interact with and function as transcriptional coactivators of BRCA1
IRE-iron-responsive element
DHFR (Dihydrofolate Reductase) PROTEIN
CBP – INHBIT HISTONE ACTEYLTRANFERRASE
PRC2-POLYCOMB REMODALLING COMPLEX2
TLS-RNA BINDING PROTEIN
Beta-secretase 1 (BACE1), also known as beta-site amyloid precursor protein cleaving enzyme 1
amyloid precursor protein (APP)
CELL MEMBRANE BOUND FRAGMENT C99 CUT BY Y SECRETASE
PVT1-Plasmacytoma Variant Translocation 1 LincRNA
Hepatocellular carcinoma (HCC), also called malignant hepatoma, is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitis infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of liver cirrhosis).
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals. It differs considerably among species anatomically, chemically, and physiologically.
The function of the prostate is to secrete a slightly alkaline fluid, milky or white in appearance, that in humans usually
Oncofetal antigens are proteins which are typically present only during fetal development but are found in adults with certain kinds of cancer.
Several studies have reported that lncRNA also play important role in Cancer development and progression. And this also opens up a large pool of unexplored science. One such report is that of lncRNA PVT1 having role in leukemic cell proliferation, which was studied in the year 2015. In the same year, another study reported that Linc0015 play role in gene expression regulation, and is involved in development of gastric cancer.
a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes.
Stomach cancer, also known as gastric cancer, is cancer developing from the lining of the stomach
PVT1-Plasmacytoma Variant Translocation 1 LincRNA
A promyelocyte (or progranulocyte) is a granulocyte precursor, developing from the myeloblast and developing into the myelocyt
Malat1 (metastasis associated lung adenocarcinoma transcript 1),
ANRIL: Antisense noncoding RNA in the INK4 locus
Myocardial Infarction Associated Transcript -MIAT
strong association between several ANRIL SNP loci and MI
lncRNAs hypoxia-inducible factor 1A antisense RNA 2, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1)
are characterized by pathological widening of the vessel and thinning of the vessel wall
Atherosclerosis-a disease of the arteries characterized by the deposition of fatty material on their inner walls.
Aneurysm-n excessive localized swelling of the wall of an artery
Myocardial infraction -a heart attack.
Hypertension - abnormally high blood pressure.
ASOs function by basepairing to the target RNAs, resulting in transcript-specific RNase H-mediated catalytic degradation
antisense oligonucleotides (ASOs)