The Svedberg Award 2006
Piergiorgio Percipalle
Department of Cell and Molecular Biology, Karolinska Institutet
Background
After graduating in Chemistry, I started my PhD at the International
Centre for Genetic Engineering and Biotechnology, Trieste, where I
worked on the molecular mechanisms of protein-DNA recognition using
chemical, biochemical and biophysical assays. I obtained my PhD in
molecular genetics at the International School for Advanced Studies
with a thesis entitled “Engineering DNA-binding proteins based on the
helix-turn-helix motif”. I then moved to the MRC Laboratory of
Molecular Biology, Cambridge, where I did a postdoc in the laboratory
of Daniela Rhodes. In Daniela’s lab I mapped some of the
protein-protein interactions that take place during protein import into
the cell nucleus. That period was very creative for me since I started
thinking about why actin is imported into the cell nucleus where it is
such an abundant protein (about 15% of cellular actin is present in the
cell nucleus). I then moved to the Karolinska Institutet in the
laboratory of Bertil Daneholt where I became acquainted with the
polytene chromosomes of the dipteran insect Chironomus tentans, ideal
to study gene expression in situ. In that period, the polytene
chromosomes turned out to be instrumental to establish that actin is in
active transcription sites and it is a genuine component of nascent
pre-messenger-ribonucleoprotein (pre-mRNP) particles. In January 2004,
I became a principal investigator in the Department of Cell and
Molecular Biology (CMB) at the Karolinska Institutet. Since then, we
have shown that actin is an essential transcription factor in both RNA
polymerase I (pol I) and RNA polymerase II (pol II)-mediated
transcription.
Research
The research in my group focuses on the mechanisms of transcriptional
and post-transcriptional control of gene expression. We are studying
both normal cells and cancer cells where these mechanisms are
profoundly affected and deregulated, leading to disruption of
controlled gene activity and malignant cell transformation.
One of our main interests is to understand the crosstalk between
transcription apparatus and dynamic alterations of chromatin structure
which are mediated by chromatin remodelling complexes and histone
modifying enzymes. These factors are recruited on active genes through
complex relay mechanisms which are not yet fully understood. Several
independent studies have shown that nuclear actin may perform a pivotal
role in this dynamic recruitment since it is present in certain
ATP-dependent chromatin remodelling complexes, in pre-mRNP particles
and it is associated with all three eukaryotic RNA polymerases. Some
mechanistic insights came from the discovery of nuclear actin-binding
proteins. In ribosomal gene transcription, the interaction between
actin and nuclear myosin 1 (NM1) is required to recruit the novel
chromatin remodelling complex B-WICH, an activator of pol I
transcription elongation. On the other hand, pol II transcription
requires the interaction between actin and the heterogeneous
ribonucleoprotein hnRNP U. This mechanism appears to be conserved from
humans to insects and is likely to be required for the recruitment of
specific histone acetyl transferases to maintain a productive pol II
transcription elongation phase. Based on the above observations, we
have proposed that actin functions in molecular switches as an
allosteric regulator of RNA polymerase-mediated transcription.
Molecular switches may represent a means of recruiting co-factors on
active genes, with the help of specific adaptors, NM1 in pol I
transcription and hnRNP U in pol II transcription.
This model raises many intriguing questions. We are currently focusing
on two of them, namely “what is the polymerization state of actin
during its function along actively transcribed genes?” and “are
actin-based molecular switches required only for transcription or they
are also utilized down-stream for post-transcriptional control of gene
expression?
Selected references
Percipalle P * (2007) Genetic connections of the
actin cytoskeleton and beyond. BioEssays,
in press
Percipalle P *, Östlund Farrants A-K (2006)
Chromatin remodelling and transcription:
Be-WICHed by nuclear myosin 1. Current Opinion Cell Biology,
18: 267-274
Percipalle P *, Visa N (2006) Molecular functions of
nuclear actin. J Cell Biol, 172:
967-971
Percipalle P *, Fomproix N, Cavellan E, Voit R,
Reimer G, Krüger T, Thyberg J, Scheer U, Grummt I, Östlund Farrants A-K
(2006) The chromatin remodelling complex WSTF-SNF2h interacts with
nuclear myosin 1and serves a role in RNA polymerase I transcription.
EMBO Reports 7: 525-530
Kukalev A, Nord Y, Palmberg C, Bergman T, Percipalle P
* (2005) Actin and hnRNP U cooperate for productive transcription by
RNA polymerase II. 2004. Nature Struct Mol Biol 12:
238-244
Percipalle P, Fomproix N, Kylberg K, Miralles M,
Björkroth B, Daneholt B, Visa N (2003) An actin-ribonucleoprotein
interaction is involved in transcription by RNA polymerase II. Proc. Natl
Acad Sci USA 100: 6475-6480