Long non coding RNA and Their clinical perspective

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

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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… 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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.
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

• 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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• 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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• 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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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)

lncRNA
Intergenic
lncRNA
Intronic
lncRNA
Sense
lncRNA
Antisense
lncRNA
According to their
genomic context
and location
LncRNA are mainly
classified into four
types:-
Classification Of lncRNA
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Intergenic lncRNA
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Source :- (Ma et al., 2013)

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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Anti Sense lncRNA
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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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The busy
lifetimes of
certain
lncRNAs
vary from
those of
mRNAs
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Source - (Quinn and Chang, 2015)

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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 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

 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
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.

• 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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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

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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•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

LncRNA Function
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Source :- (Mercer et al., 2009)

The Roles Of lncRNAs In Complex Human Diseases
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Source :- (Li et al., 2014)

Role of lncRNA in Alzheimer’s
4/2/2016 8:03 AM 25Source:- ( Faghihi et al., 2008 )

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lncRNAs In Cancer

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lncRNAs In CANCER

lncRNAs in Cardiovascular Diseases
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Source:-(Jiang and Ning, 2015)

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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

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),
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Chung, S., Nakagawa, H., Uemura, M., Piao, L., Ashikawa, K., Hosono, N., ... & Tsunoda, T. (2011).
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Zhao, J., Liu, Y., Zhang, W., Zhou, Z., Wu, J., Cui, P., ... & Huang, G. (2015). Long non-coding RNA Linc00152 is
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Zeng, C., Yu, X., Lai, J., Yang, L., Chen, S., and Li, Y. (2015). Overexpression of the long non-coding RNA PVT1 is
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