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PhD Defence: Nikolai Hecker |
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2016-09-19: RNA secondary structure flexibility and gene regulation inside the human brain. The defence will take place on Sep 19th, 13:15-16.15 in Festauditoriet (Aud. A1-01.01), Bülowsvej 17, 1870 Frederiksberg C.
Everybody is welcome. Registration is not necessary.
Reception around 16:15 at the Library (buliding 1.04), Grønnegårdvej 7, DK-1870 Frederiksberg C
Assessment Committee:
(Chairperson) Professor Thomas Litman
Associate Professor Kay Nieselt
Professor Daniel Gautheret
Supervisor: Professor Jan Gorodkin
Abstract
Transcriptional and post-transcriptional regulation of gene expression is essential for the fate and function of any cell in eukaryotes and of bacteria. Through gene regulation, eukaryotes are able to develop diverse tissues with distinct and complex functions such as the human brain. Two of the most important features of gene regulation are transcription factors and regulatory elements inside mRNAs. Folding into RNA structures is necessary for some of these regulatory elements to be functional. For such regulatory elements, the sequence composition including flanking regions formed by adjacent nucleotides may impact folding into the proper RNA structure. Other RNA structures such as riboswitches, a class of regulatory elements in bacteria, rely on the dynamic rearrangement of RNA structures for altering gene expression.
In this PhD project, potential features involved in gene regulation of human brain tissues were investigated and the flexibility of RNA secondary structures was examined in two different contexts.
The impact of flanking regions towards folding into a specified RNA secondary structure was studied for regulatory elements in mRNAs and novel RNA structure predictions. For this purpose, a computational approach, RNAcop, was developed for assessing and optimizing flanking regions. Optimizing flanking regions can be in particular relevant for in vitro RNA folding experiments that require extracting a smaller structured RNA fragment from a large transcript, e.g. a regulatory element from a mRNA. The results of the computational analysis supported by in vitro experiments indicate that different flanking regions influence the probability towards folding into a specified structure for the majority of structures. Optimizing flanking regions may be crucial for examining at least 4% of the analyzed RNA structures. For studying RNA secondary structure dynamics, the computational framework FRETtranslator was developed. FRETtranslator combines RNA secondary structure kinetics and RNA 3D structure sampling into a HMM for decoding smFRET time series into sequences RNA secondary structures. The structural transition of a preQ1-riboswitch was successfully predicted by FRETtranslator and FRETtranslator holds the potential to investigate RNA structure transitions of more complex RNAs.
Another part of this PhD project is concerned with gene regulation inside the human brain. Thirteen transcription factors that show a localized contribution to gene expression in a specific brain tissue and four transcriptions factors with globally strong contributions to gene expression were identified based on a regression approach. Several of these transcription factors could be associated with relevant functions for the human brain. Potentially related to post-transcriptional regulation, differentially expressed genes in different brain tissues showed an enrichment for known regulatory elements such as RNA-protein binding sites or AU-rich elements including regulatory elements that overlap RNA secondary structure predictions. Using these sets of enriched regulatory elements, four RNA secondary structure motifs were identified that are potentially involved in the regulation of gene expression. In another contribution of this PhD project, approaches based on phylogenetic conservation for predicting RNA-protein binding sites and RNA-RNA interactions that are potentially involved in regulation of a transcript are demonstrated on the example of a ncRNA which may play a role in cerebellar ataxia.