ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Matthias W.
Hentze
MD 198, University of
Münster.
Postdoctoral training at the
NIH, Bethesda.
Group leader at EMBL since
1989; Senior Scientist since
1998. Co-Director of the
EMBL/University of
Heidelberg Molecular
Medicine Partnership Unit
since 2002. Associate
Director since 2005.
Cytoplasmic gene regulation and molecular medicine
Previous and current research
Important steps in the control of gene expression are executed in the cytoplasm: the regulation of
mRNA translation and stability. We are elucidating these regulatory mechanisms, including the
function of miRNAs, which has become a very active focus of our work (figure 1). We use mostly
biochemical approaches and mammalian, yeast and Drosophila model systems.
Within the Molecular Medicine Partnership Unit (MMPU), we are investigating the posttranscriptional
processes of nonsense-mediated decay (NMD) and 3’ end processing and their importance
in genetic diseases (with Andreas Kulozik). We also study the role of miRNAs in cancer
and other diseases (with Andreas Kulozik and Martina Muckenthaler).
Our second major interest
is the systems
biology of mammalian
iron metabolism
(figure 2). This
work includes the system-wide
exploration
of the functions of the
IRE/IRP regulatory
network. Within the
MMPU (with Martina
Muckenthaler),
Figure 1: A two-hit model explaining miR-mediated repression.
we study the molecular basis of genetic and non-genetic diseases of human iron metabolism. Our work employs conditional knockout mouse
strains for IRP1 and IRP2 and mouse models of iron metabolism diseases. We also use a unique DNA microarray platform (the IronChip)
that we have developed.
Future projects and goals
• To uncover the basic mechanisms underlying protein synthesis
and its regulation by miRNAs and RNA-binding
proteins in cell metabolism, differentiation and development.
• To help elucidate the role of RNA metabolism in disease,
and to develop novel diagnostic and therapeutic strategies
based on this knowledge.
• To understand the molecular mechanisms and regulatory
circuits to maintain physiological iron homeostasis and its
connections to the immune system.
• To contribute to the elucidation of the molecular pathophysiology
of common iron overload (haemochromatosis),
iron deficiency (anaemia) and iron management (anaemia,
Parkinson's disease) disorders.
For research themes and projects of the teams in the MMPU, see The
Molecular Medicine Partnership Unit (MMPU), University Hospital
Heidelberg and www.embl.org/research/partners/mmpu/index.html.
Figure 2: Systems biology of mammalian iron metabolism.
Selected references
Galy, B., Ferring-Appel, D., Kaden, S., Grone, H.J. & Hentze, M.W.
(2008). Iron regulatory proteins are essential for intestinal function
and control key iron absorption molecules in the duodenum. Cell
Metab., 7, 79-85
Thermann, R. & Hentze, M.W. (2007). Drosophila miR2 induces
pseudo-polysomes and inhibits translation initiation. Nature, 7,
875-878
Beckmann, K., Grskovic, M., Gebauer, F. & Hentze, M.W. (2005). A
dual inhibitory mechanism restricts msl-2 mRNA translation for
dosage compensation in Drosophila. Cell, 122, 529-50
Hentze, M.W., Muckenthaler, M.U. & Andrews, N.C. (200).
Balancing acts: molecular control of mammalian iron metabolism.
Cell, 117, 285-297
5