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Inherited non-coding RNA RNAs from the same locus. Besides studies into
Multicellular organisms start from a single cell these specific ncRNAs, we also explored publicly
that divides repeatedly to form a mass of cells available transcriptomics data to identify a
which eventually differentiate into tissues and highly correlated expression pattern of
specific cell types while adopting highly hundreds of ncRNAs in the sperm and oocyte.
restricted gene expression patterns. ncRNAs, These observations suggest that inherited RNAs
along with chromatin modifiers and are a significant component of the cellular
transcription factors form the three main milieu in the early stages of zygotic
regulators of this process. We speculated that development.
ncRNAs maybe inherited from the gametes and
by virtue of their stability may modify zygotic Polyglutamine disease
gene expression. To explore this novel form of Polyglutamine diseases are a class of late onset,
epigenetic inheritance in further depth, we hereditary diseases marked by selective
carried out a combination of bioinformatics and neurodegeneration in specific brain regions.
experimental analysis in the vertebrate model Each polyglutamine disease is caused by a
system, zebrafish. Zebrafish combines several mutation leading to an expansion of a CAG
desirable features: transparent embryos, rapid triplet repeat within the coding region of a gene.
development of organs, external fertilization, The expanded CAG triplet repeat encodes a
amenability to micro-injection of RNAs at the polyglutamine stretch in the protein which leads
single cell stage and delayed activation of to protein aggregation and neuronal cell death,
zygotic transcription. We have previously the twin hallmarks of these diseases. One such
demonstrated the inheritance of a microRNA, disease, Spinocerebellar Ataxia17 (SCA17) is
miR-34 and a lncRNA, Cyrano. Perturbations to associated with polyglutamine expansion within
the inherited pool of these ncRNAs led to the ubiquitous general transcription factor,
defects in brain development. We also reported TATA binding protein, henceforth called polyQ-
a novel lncRNA, christened Durga, arising from TBP. We have previously reported that polyQ-
the 5’end of the Kalrn locus in the zebrafish TBP expression and aggregation in the rodent
genome. We explored the functional role of cell line Neuro2A leads to release of interferon
Durga in greater detail by studying the effect of by the cells, aberrant expression of interferon
its over-expression. Over-expression of the pathway genes, apoptotic miRNAs and
lncRNA led to changes in the activating histone eventually cell death. Since CAG repeats in non-
mark, H3K27ac at the Kalrn locus, suggesting coding regions are also known to cause similar
that it may facilitate the action of chromatin effects, we speculated that CAG RNA and not
modifiers. Pharmacological inhibitors of GCN5 polyQ protein maybe the fundamental
abolished the effect of Durga lncRNA at the pathological entity. To explore this possibility
Kalrn locus. On the basis of these findings, we further, we created mutated versions of the
speculate that Durga RNA can facilitate polyQ-TBP gene that compromise its protein
chromatin modifications at select loci, in coding potential but continue to express the
collaboration with histone modifiers. We CAG repeat containing mRNA. Several different
explored the mouse genome to understand approaches to placing CAG repeat RNAs inside
Durga-like ncRNAs arising from the Kalrn locus. cultured neuronal cells, converged on two key
In the mouse genome, we found several findings. Firstly, CAG repeat RNA was not
overlapping coding and non-coding transcripts sufficient to cause the neurodegeneration,
within the Kalrn locus. The expression pattern of suggesting that prima facie, RNA toxicity was
the ncRNAs change dynamically during not the underlying cause for neuronal cell
differentiation of primary neurons in culture, death. However, the CAG RNA was
coinciding in time with changes in the coding immunoprecipitated with certain proteins
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