of the Max - MDC

Genetics, Genomics, Bioinformatics,
and Metabolism
Coordinator: Nikolaus Rajewsky
Systems Biology of Gene
Regulatory Elements
Nikolaus Rajewsky
My lab uses computational and experimental methods to dissect, systems-wide, function and
evolution of gene regulation in metazoans. One major focus is to understand more about gene
regulation by small RNAs, in particular microRNAs. We are developing predictive models for the targets
of microRNAs. To probe general mechanisms of gene regulation of microRNAs, we work in cell
lines. We are also investigating the function of small RNAs during very early development of C. elegans.
Furthermore, we have established planaria as a model system in our lab. These freshwater flatworms
are famous for their almost unlimited ability to regenerate any tissue via pluripotent, adult
stem cells. We are studying the role of small RNAs in planarian regeneration.
Introduction
A major lesson from recent genomics is that metazoans
share to a large degree the same repertoire of proteinencoding
genes. It is thought that differences between cells
within a species, between species, or between healthy and
diseased animals are in many cases due to differences in
when, where and how genes are turned on or off. Gene regulatory
information is to a large degree hardwired into the
non-coding parts of the genome. Our lab focuses on decoding
transcriptional regulation (identification and characterization
of targets of transcription factors in non-coding
DNA) and post-transcriptional control mediated by a class of
small, non-coding RNAs (microRNAs). microRNAs are a
recently discovered large class of regulatory genes, present
in virtually all metazoans. They have been shown to bind to
specific cis-regulatory sites in 3’ untranslated regions (3’
UTRs) of protein-encoding mRNAs and, by unknown mechanisms,
to repress protein production of their target mRNAs.
Our understanding of the biological function of animal
microRNAs is just beginning to emerge, but it is clear that
microRNAs are regulating or involved in a large variety of
biological processes and human diseases, such as developmental
timing, long-term memory, signalling, homeostasis
of key metabolic gene products such as cholesterol, apoptosis,
onset of cancer, Tourette’s syndrome, and others.
Systems Biology of Gene Regulation
Catherine Adamidi, Kevin Chen, Teresa Colombo, Minnie
Fang, Marc Friedlaender, Signe Knespel, Azra Krek,
Andreas Kuntzagk, Svetlana Lebedeva, Tatjana
Luganskaja, Jonas Maaskola, Marlon Stoeckius, Nadine
Thierfelder)
It is clear that a better understanding of gene regulation
and in particular of the just emerging universe of non-coding
RNAs can only come by integrating various data sources
(comparative sequence analysis, mRNA expression data,
protein-protein interactions, mutant phenotypes from RNAi
screens, polymorphism data, experimentally defined gene
regulatory networks, ChIP-chip data, etc) since each data
source alone is only a partial description of how cells function.
For example, to understand microRNA function, we not
only need to identify their targets but also to decode how
microRNAs are transcriptionally regulated. A major focus of
the lab is therefore in developing methods that integrate
different data sources and methods to produce global and
yet specific predictions about how, when, and where gene
are regulated. This will ultimately lead to the identification
and functional description of gene regulatory networks. We
will continue to test, develop and “translate” these methods
and their predictions using specific biological systems, such
Cardiovascular and Metabolic Disease Research 51