Objective
"miRNAs are small RNAs that guide the RNA-induced silencing complex to
mRNA targets, destabilizing them and inhibiting their
translation. Much has been learned about their involvement in organism
development and function, yet some striking puzzles remain. On the one
hand it has been shown that miRNAs are essential for development, and
the preferential targeting of transcription factors (TFs) by miRNAs
suggests that miRNAs and TFs ""coordinate"" to regulate gene
expression. Furthermore, studies in the past year concluded that, on
their own or in combination with TFs, miRNAs can induce reprogramming
of somatic cells into induced pluripotent stem cells (iPSC). On the
other hand, high-throughput measurements of mRNA and protein level
changes upon miRNA transfections suggest that miRNAs have largely a
""fine-tuning"" function. These small effects on individual genes must,
however, confer a substantial selective advantage, because many target
sites remain conserved over long evolutionary distances. Here I first
propose to investigate the hypothesis that instead of primarily
affecting the average levels of target genes, miRNAs reduce the
cell-to-cell variation in gene expression, affecting
precisely the steps that determine the intrinsic noise. I will then
use miRNA-mediated reprogramming of somatic cells into iPSCs as a
model system to directly investigate the ""coordination"" between miRNAs
and TFs in determining cell identity and differentiation. Through
determination of miRNA targets with Argonaute crosslinking and
immunoprecipitation, mRNA sequencing and methylated DNA
immunoprecipitation I attempt to retrace the regulatory interactions
that lead from induction of a few miRNAs, through perturbation of TF
activities, to the activation of ""stemness"" genes. Finally, following
up on preliminary results obtained in my lab, I will investigate the
function of miRNA targeting in the nucleus, that potentially couples
transcriptional and post-transcriptional regulation more directly."
Fields of science
Call for proposal
ERC-2012-StG_20111109
See other projects for this call
Funding Scheme
ERC-SG - ERC Starting GrantHost institution
4051 Basel
Switzerland