Regulation of gene expression in neuronal tissue by RNA interference and editing

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandling

  • Morten Trillingsgaard Venø, Danmark
No tissue in the mammalian organism is more complex than the brain. This complexity is in part the result of precise timing and interplay of a large number mechanisms modulating gene expression post-transcriptionally. Fine-tuning mechanisms such as A-to-I editing of RNA transcripts and regulation mediated by microRNAs are crucial for the correct function of the mammalian brain.

We are addressing A-to-I editing and regulation by microRNAs with spatio-temporal resolution in the embryonic porcine brain by Solexa sequencing of microRNAs and 454 sequencing of edited neuronal messenger RNAs, resulting in detailed data of both of these fine-tuning mechanisms in the embryonic development of the pig. Editing levels of transcripts examined are generally seen to increase through development, in agreement with editing of specific microRNA also examined in the Solexa sequencing study.

Three studies examining microRNA expression and targeting, specifically in neurons of knockout mice or transgenic mice, were also performed. One study revealed that disrupting the expression of Argonaute2, the main effector of miRNA function, leads to a reduction of the microRNA abundance for a specific subset of microRNAs, causing these transgenic mice to be less prone to cocaine addictive behavior. Another study demonstrated that abolishing the expression of histone methylases, GLP and G9a, increases the expression level of a large number of miRNAs. A possible feed-back mechanism is suggested, since a subset of these miRNAs is able to target the GLP 3’ untranslated region, causing reduced expression of the targeted transcript. In the third study a procedure for global detection of microRNA targeting specifically in neurons is demonstrated, using Solexa sequencing of microRNA and messenger RNA segments binding to Argonaute2.

Altogether, this dissertation provides data, generated mainly through deep sequencing methodologies, on RNA editing and microRNA expression and targeting in brain tissues.
OriginalsprogEngelsk
ForlagAarhus University, Faculty of Science and Technology
Antal sider188
StatusUdgivet - 27 mar. 2012

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