MicroRNAs Tune Protein Synthesis

Researchers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, have generated new findings on how microRNAs (miRNA) regulate protein expression. Two teams lead by Matthias Selbach (Proteomics) and Nikolaus Rajewsky (Systems Biology) have shown that a single miRNA can directly regulate synthesis of hundreds of different proteins. In this way, miRNAs can program the way human cells act, they report in the latest issue of the journal Nature (doi:10.1038/nature07228)*.

All body
cells contain the same genes, may they be muscle-, brain-, blood-, or liver
cells. Therefore, all have the same blue prints for the production of proteins.
However, different cells produce different proteins at different times – a
prerequisite for the body to develop normally and stay healthy. For this to
happen, genes must be regulated differently in different cell types - that is,
turned on and off at the right time. Only a few years ago, researchers
discovered that miRNAs play an important role in gene regulation and, thus,
help determine which proteins are produced by which cells.

Proteins
are the building and
operating materials of life and are required for the structure, function, and regulation of the body's
cells, tissues, and organs. Diseases can result if protein production goes
awry. Worldwide,
scientists are seeking to develop methods to detect which miRNAs are active in
tissue samples and which proteins are regulated by them. To date, researchers
have identified a few hundred human miRNAs but it is not clear which proteins
they regulate. A further complication is that miRNAs are known to regulate
synthesis of proteins, which is difficult to measure.

Using a
novel experimental approach carried out by PhD students Björn Schwanhäusser and
Nadine Thierfelder, the MDC researchers for the first time were able to
quantify protein synthesis for thousands of different human proteins. Together
with extensive computational analyses, they could further identify and quantify
the direct impact of specific miRNAs on target protein synthesis.

Changing the fate of a cell

The MDC
researchers could demonstrate that the regulation of protein synthesis
typically is mild, with a number of interesting exceptions. “MicroRNAs screw
many switches, but most of them only slightly”, Matthias Selbach explains.
“Thus the system is robust and flexible. A single miRNA can have profound
impact on the fate of a cell. MiRNAs active in cancer cells, for example, are
different from those active in normal cells.”

Using a
trick, the MDC researchers were for the first time able to measure changes in
protein production after artificially changing the activity of specific miRNAs.
They labeled amino acids (the building blocks of
proteins) with a stable, non-radioactive isotope and put it together with miRNA
in cell culture. This allowed them to distinguish labeled proteins in a mass spectrometer.
They could show that only newly produced proteins were heavier.

A single miRNA can tune the protein levels of
thousands of genes

The MDC
researchers also compared the impact on protein production when artificially
boosting or repressing the activity of an individual miRNA. They found that
this impact is largely inverse for thousands of different proteins. Thus, ‘it
is as if a single miRNA can alter a large fraction of the entire protein
production program of a human cell in a reversible fashion’, comments Nikolaus
Rajewsky.

The
findings of the two Berlin research teams in collaboration with Raya Khanin
from Glasgow University (UK) are anticipated to have a big impact in the
future, as miRNAs are considered to be promising diagnostic and therapeutic
candidates for the treatment of human diseases.

*Widespread
changes in protein synthesis induced by microRNAs’

Matthias Selbach¹, Björn
Schwanhäusser^1,2, Nadine Thierfelder^1,2, Zhuo Fang¹,
Raya Khanin³, and Nikolaus Rajewsky¹

1 Max Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, Berlin, Germany

3 Department of Statistics, 15 University
Gardens, University of Glasgow, UK

2 These authors contributed equally to the work

1st row from left: Zhuo Fang and Björn Schwanhäusser 2nd row from left: Nadine Thierfelder 3rd row from left: Professor Nikolaus Rajewsky and Dr. Matthias Selbach (Photo: Jonas Maaskola/ Copyright: MDC)

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/