MECHANISM OF miRNA ACTIVITY REGULATION IN MAMMALIAN CELLS
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
MECHANISM OF miRNA ACTIVITY REGULATION
IN MAMMALIAN CELLS
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| Creator |
Bose, Mainak
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| Subject |
Molecular & Human Genetics
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| Description |
Cells must be able to respond to changes in their microenvironment in order to
survive. Genes encode proteins and proteins dictate cell function. Information flows
from DNA to RNA to protein, according to the central dogma of molecular biology
and each of the steps are under stringent regulatory control to ensure cell fate and
function. Cells can control which genes get transcribed and which transcripts get
translated. Regulation of the two major steps — transcription and translation — is
critical to its adaptability. Regulation of transcription and translation occurs in both
prokaryotes and eukaryotes, but it is far more complex in eukaryotes.
MicroRNAs (miRNAs) are a class of small non-coding RNAs that posttranscriptionally
regulate gene expression via translational repression and/or mRNA
degradation. These tiny regulators search for cognate targets by base pairing with
the 3’UTR of the target mRNAs. Over the years, since its discovery the role of
miRNAs has become apparent in regulating developmental timing, host-pathogen
interactions as well as cell differentiation, proliferation, apoptosis, tumorigenesis,
etc. Just like any other regulatory element, the biogenesis, activity and turnover of
miRNAs themselves are under strict regulatory control.
Extensive research has established how miRNAs regulate target mRNAs by
translation repression. However, information regarding the effect of target mRNA on
biogenesis and stability of corresponding miRNAs is limited. In this study, we have
reported increased biogenesis of cognate miRNAs in presence of abundant amounts of target mRNA in both cells as well as cell-free in vitro system. These
miRNAs get loaded onto AGO2 to form functionally competent miRISCs. This
target-driven miRNA increase is proportional to the concentration of target mRNA
and is affected by the translatability of the target message. While investigating the
molecular mechanism of the phenomenon, we identified that increased pre-miRNA
processing by AGO2-associated DICER1 in presence of target mRNA, contributes
to this increased miRNP formation.
Compartmentalization of biological processes provides a mechanism of
regulation of the processes with exquisite spatial and temporal control. We have
observed that miRNA activity is compartmentalized on the rough Endoplasmic
Reticulum (rER) membranes in human cells and have explored the effects of this
compartmentalization on miRNA function. Probing further into the phenomenon of
target driven miRNA biogenesis, we identified the rER membranes as the site of
target mRNA-governed miRNA assembly in human cells.
It is likely that target driven miRNA biogenesis operates in addition to the
conventional process of repression by preformed miRNPs. Rather than
transcriptionally upregulating miRNA synthesis, modulating the final step of
biogenesis will serve as an immediate means to increase miRNA production. This
in turn will help the cell respond to specific and urgent cellular needs like rapid
target driven miR-122 biogenesis during starvation stress reversal in human hepatic
cells. Thus, we have identified an additional layer of post-transcriptional regulation
of gene expression that helps the cell to maintain requisite levels of mature forms of
respective miRNAs by modulating its synthesis depending on target availability.
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| Date |
2017
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2773/1/Thesis_MainakBose.pdf
Bose, Mainak (2017) MECHANISM OF miRNA ACTIVITY REGULATION IN MAMMALIAN CELLS. PhD thesis, University of Calcutta. |
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| Relation |
http://www.eprints.iicb.res.in/2773/
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