ayout 1 - EMBL Grenoble

EMBL Monterotondo
Transcription factor function in development,
physiology and disease
Transcription factors play important roles in regulation of cellular proliferation, differentiation and
in the function of fully differentiated cells. We look at how transcription factors link the processes
of cellular differentiation and self-renewal/proliferation, both at the stem cell level and during terminal
cellular differentiation. We use mouse genetics to study in vivo the C/EBP family of basic region
leucine zipper transcription factors, proteins which play essential roles in the development of
the hematopoietic system, adipose tissues, epithelia and granulosa cells. We use conditional mutagenesis
to delete one or more C/EBPs from specific cell types, and point mutagenesis to specifically
alter C/EBP protein-protein interactions or post-translational modifications.
Previous and current research
We previously defined E2F repression and interaction with the SWI/SNF complex as C/EBPα functions
essential for adipose and myeloid differentiation (Pedersen et al., 2001, Genes & Dev. 15;
Porse et al., 2001, Cell, 107). We have now found that E2F repression is required also for myeloid
tumour suppression, as mice homozygous for mutations that disable C/EBPα-E2F interaction have
increased myeloid progenitor proliferation and develop an acute myeloid leukemia (AML)-like
disease (Porse et al., 2005). In contrast, we did not observe any effect on progenitor proliferation
upon deletion of the Cdk2/Cdk4 interaction domain of C/EBPα (Porse et al., 2006). Mutations in
the gene encoding C/EBPα are found in AML patients, and the most common type results in specific
loss of the 42kDa C/EBPα isoform (p42), while preserving expression
of the 30kDa isoform (p30). Only p42 has E2F repression activity,
and when we generated p42 knockout mice we found that also these developed
AML. We are now generating knockin mice with other AMLderived
mutations, and investigating the role of C/EBPα mutations in
the formation of self-renewing leukemic stem cells. We are currently investigating
the role of C/EBPs in keratinocytes, and have observed a
similar role for C/EBPs in the transition from proliferation to differentiation;
however, in this case C/EBPα and C/EBPβ function redundantly,
and removal of both is necessary to cause keratinocyte hyperproliferation
and impair their differentiation (see figure). Other main projects involve
studying the role of post-translational modifications of C/EBPs in
metabolism and macrophage activation, and the transcriptional regulation
of C/EBPβ.
Claus Nerlov
PhD 1995, University of
Copenhagen.
Postdoctoral research at
EMBL Heidelberg.
Head of Laboratory of Gene
Therapy Research,
Copenhagen Uni. Hospital.
Group leader at EMBL since
2001.
Visiting Professor, Stem Cell
Center, University of Lund,
Sweden from 2005.
Future projects and goals
The future focus of the laboratory will be to elucidate the
molecular mechanisms by which C/EBPs control differentiation
in non-hematopoietic tissues (neurons, skin,
liver), and to determine the signalling pathways that regulate
C/EBPs through post-translational modification. A
major effort will deal with the effects of leukemogenic mutations
on hematopoietic stem cell function, in order to
determine how malignant, self-renewing tumour stem
cells arise.
Defective keratinocyte differentiation and epidermal hyperplasia upon conditional
ablation of C/EBPα and C/EBPβ expression in the skin. A) Skin sections from
control mice (carrying floxed alleles of both C/EBPα and β, but not the keratin 14-
Cre transgene; upper panel) and C/EBPα/β double knockout mice (lower panel; as
above, but with the K14-Cre transgene). The sections were stained with antibodies
against the basal cell marker (keratin 14, green), a marker for differentiating
keratinocytes (keratin 10, red) and the DNA stain DAPI (blue). The lower boundary
of the epidermis is defined by the keratin 14 positive basal cells; the outer surface
of the skin is at the top of the panels. Note the expansion of the keratin 14
expression domain and diminished keratin 10 expression in double knockout mice.
B) Skin sections as in A), stained with antibodies against keratin 14 (green) and
proliferating cell nuclear antigen (PCNA, a marker of proliferating cells; red). Note
the expanded domain of cell proliferation in double knockout mice.
Selected references
Kirstetter, P., Schuster, M.B., Bereshchenko, O., Moore, S., Dvinge,
H., Kurz, E., Theilgaard-Monch, K., Mansson, R., Pedersen, T.A.,
Pabst, T., Schrock, E., Porse, B.T., Jacobsen, S.E., Bertone, P.,
Tenen, D.G. & Nerlov, C. (2008). Modeling of C/EBPα mutant acute
myeloid leukemia reveals a common expression signature of
committed myeloid leukemia-initiating cells. Cancer Cell, 13, 299-
310
Nerlov, C. (2007). The C/EBP family of transcription factors: a
paradigm for interaction between gene expression and proliferation
control. Trends Cell Biol., 17, 318-32
Kirstetter, P., Anderson, K., Porse, B.T., Jacobsen, S.E. & Nerlov, C.
(2006). Activation of the canonical Wnt pathway leads to loss of
hematopoietic stem cell repopulation and multilineage differentiation
block. Nat. Immunol., 7, 108-1056
Porse, B.T., Bryder, D., Theilgaard-Monch, K., Hasemann, M.S.,
Anderson, K., Damgaard, I., Jacobsen, S.E. & Nerlov, C. (2005). Loss
of C/EBPα cell cycle control increases myeloid progenitor
proliferation and transforms the neutrophil granulocyte lineage. J.
Exp. Med., 202, 85-96
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