Cell News 02/2017
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We have recently uncovered a fundamental molecular mechanism
for this process in epidermal SCs, where we observe that extrin-
sic forces modulate chromatin compaction and epigenetic gene
silencing through actin-dependent remodeling of the nuclear
envelope (Le et al., 2016). To decipher how mechanical forces
regulate SC identity, we sought to identify pathways that respond
to force and establish their functional significance in SC fate
determination. We observed that a mechanosensory complex of
emerin (Emd), non-muscle myosin IIA (NMIIA) and actin relays ex-
trinsic mechanical forces to the nucleus to control gene silencing
and chromatin compaction state (Le et al., 2016).
Functionally, chromatin condensation typically results in gene
silencing, while allowing the selective access of the transcription
machinery to some lineage-specific and constitutively expressed
genes within euchromatin (Pombo and Dillon, 2015; Tessarz and
Kouzarides, 2014). Yet, such nuclear rearrangements also have
direct implications for the cellular response to mechanical cues. It
has been observed that densely packed heterochromatin and more
loosely packed euchromatin have different mechanical proper-
ties. Specifically, the nuclear interior becomes more viscous and
deformable upon decondensation of the tightly-packed heteroch-
romatin (Chalut et al., 2012; Spagnol and Dahl, 2016). We observe
that force-driven enrichment of Emd at the outer nuclear mem-
brane of epidermal stem cells leads to defective heterochromatin
anchoring to the nuclear lamina, and a switch from H3K9me2,3
to H3K27me3 occupancy at constitutive heterochromatin (Le
et al., 2016). Putting this into the context of the previous work,
we hypothesize that the switch from H3K9me2,3 to H3K27me3
occupancy could play a role in the nuclear mechanoresponse by
making the nucleus more elastic and thereby more resistant to
deformation.
A number of recent studies have expanded the role of actin be-
yond that of the cytoplasmic polymeric form, and several studies
implicate monomeric nuclear as a critical co-factor for a number
of transcription factors as well as for the RNA polymerases them-
selves (Grosse and Vartiainen, 2013; Treisman, 2013; Virtanen and
Vartiainen, 2017). Interestingly, we found that Emd enrichment at
the outer nuclear membrane is also accompanied by the recruit-
ment of NMIIA to promote local actin polymerization that reduces
nuclear actin levels, which results in attenuation of global RNA
polymerase II-mediated transcription. This global transcriptional
repression leads to accumulation of H3K27me3 at specific targets
of the polycomb repressive complex 2 (PRC2) target genes, which
in the case of epidermal SCs are the terminal differentiation
genes (Ezhkova et al., 2009; Le et al., 2016). Consequently, tran-
scription of these genes is inhibited, leading to attenuated termi-
nal differentiation of SCs in the presence of strain. Importantly,
restoring nuclear actin levels in the presence of mechanical stress
counteracts PRC2-mediated silencing of transcribed genes (Le et
al., 2016). The precise molecular mechanism(s) by which nuclear
actin regulates transcription remain open for further studies,
but this work provides initial evidence for direct coupling of
cytoskeletal and transcriptional states in response to mechanical
strain. Taken together, our results reveal how mechanical signals
integrate transcriptional regulation, chromatin organization and
nuclear architecture to control lineage commitment and nuclear
mechanoadaptation (Fig. 3).
Outlook
We will continue combining
in vivo
studies with innovative in vitro
models and apply scale-bridging technologies, from single mole-
cule-level atomic force microscopy to genome-level analysis and
in
vivo
organismal imaging, to establish quantitative principles of epi-
dermal tissue maintenance through stem cells and to identify the
key processes of ageing-induced decline. Furthermore, our ongoing
screening approaches using the 3C SC culture technology will en-
able us to identify molecular targets with direct clinical relevance.
Acknowledgements
I would like to thank all past and present members of my lab-
oratory for their fantastic work and enthusiasm towards their
projects. I would also like to thank all the great mentors that
have supported me throughout my scientific career, includ-
ing Jorma Keski-Oja, Kari Alitalo, Reinhard Fässler, Thomas
Krieg, and Carien Niessen. Research in my laboratory has been
supported by the Max Planck Society, the Max Planck Förder-
stiftung, the Behrens Weise Foundation, and the Deutsche
Forschungsgemeinschaft through SFB 829 and WI 4177/2.
About the author
Sara Wickström studied medicine at the University of Helsinki, Fin-
land, and obtained her MD in 2001. In 2004 she obtained her PhD
in the group of Jorma Keski-oja. She then moved to the Max Planck
Institute of Biochemistry, Martinsried to do her postdoctoral work
with Reinhard Fässler. Since 2010 she is a Max Planck Research
Group Leader at the Max Planck Institute for Biology of Ageing.
BINDER INNOVATION PRIZE 2017
Thomas M. Magin (DGZ), Sara A. Wickström, André Bachmann (BINDER GmbH)
