of the Max - MDC

Structure bition of differentiation. of the Group A major focus of our research is to amplifying progenitor cells. Mutations in either transcription
Group understand Leader the dynamics and Scientists the molecular mechanisms Students factor may contribute Technical to leukemia. Assistants Graduate
Secretariat
Prof. that connect Dr. Achim transcription Leutz factors Dr. Valerie in stem Begay cells, cell multi-Olplication, Pless The concept of orchestration Maria Knoblich of hematopoiesis by co-oper-
Sylvia Sibilak
and terminal differentiation.
Dr. Elisabeth Kowenz-Leutz Katrin ating Zaragoza transcription factors Christiane has since Calließ then been extended by
The chromatin of hematopoietic Dr. Jörn genes Lausen appears to be epigenetically
indexed, long before Dr. their Marina expression Scheller actually
occurs. During differentiation Dr. along Jeske a Smink given lineage, a distinct
pattern of lineage specific Dr. gene Klaus expression Wehtmar becomes
many research groups to Karolin many Friedrich* other factors in different cell
lineages. The availability Anne of an Viktoria assay Giese* to monitor activation
of endogenous genes permitted Petra Gosten-Heinrich
the molecular analysis of
how hematopoietic genes are regulated in normal and in
selected whereas other options are defeated. It appears leukemic cells. We have uncovered mechanisms how Myb
that “early” events, such as Wnt/β-catenin or Notch signaling
and C/EBP transcription factors regulate gene expression.
and early transcription factors (such as SCL and c-Myb) Recently, we have also begun to explore Wnt-signaling as
are expedient candidates for earmarking hematopoietic an important effector of hematopoietic stem cell biology
genes, whereas “late” differentiation factors (such as C/EBP and leukemogenesis.
or Pax-5, etc) are candidates for sorting out lineage specification.
Orchestration of these functions is essential for C/EBPs: ancestry, redundancy, & development
proper differentiation, as many leukemic diseases display
conflicting gene expression patterns and “multi-lineage
competence”, known as lineage infidelity. How such
hematopoietic “multi-lineage competence” is set up and
maintained in stem cells, how it is annihilated during commitment
and differentiation and why it comes up again during
leukemic conversion are major topics of our research.
Research Topics
Signaling and instructive functions of transcription
factors in hematopoiesis and leukemogenesis
Hematopoietic cell differentiation programs are executed by
switching on and off distinct sets of genes in a coordinate
fashion. Specificity is primarily achieved by regulating the
activity of transcription factors through post-translational
modifications and by combinatorial interactions between
different transcription factors. Signaling and combinatorial
interactions permit plasticity of regulation and multiple
developmental decisions to be accomplished with a limited
set of regulators.
Several years ago, we identified the first combinatorial
molecular switch that instructs even non-hematopoietic
cells, such as skin fibroblasts, to express granulocyte and
macrophage genes. Accordingly, this gene switch accomplishes
epigenetic and genetic gene regulation in heterologous
cells. The switch consists of two types of transcription
factors: CCAAT/Enhancer Binding Proteins (C/EBP) and the
product of the c-Myb proto-oncogene. C/EBPs regulate cell
cycle arrest and cell differentiation, whereas Myb is essential
for precursor cell expansion and maintenance of transit
C/EBPs comprise a family of 6 genes in vertebrates. Four
members, C/EBPα,β,δ,ε, are highly related whereas two
others, γ and ζ, are more divergent and display only
homology in their bZip region. The N-terminal parts (first
∼80 amino acids) of C/ EBPα,β,δ,ε represent strong transactivation
domains (TAD) whereas the center sequences
(aa ∼100 -200) contain regulatory domains (RD). Both, TAD
and RD, are targets of post-translational modifications.
Knockout analysis of individual C/EBPs in mice and phylogenetic
tree construction suggested that C/EBPα and C/EBPβ
are the most important ones. This notion was confirmed by
generating mice deficient for both, C/EBPα and C/EBPβ.
Loss of C/EBPα and of C/EBPβ causes placental defects in
trophoblast cells and are embyonic leathal.
Chromatin remodeling and lineage specific gene
expression
The basic unit of chromatin is the octameric histone particle
(nucleosome) that serves to package DNA. An extended
molecular protein machinery is required to adjust the structure
of chromatin and DNA for transcription or for repression,
e.g. by nucleosome toggling and covalent histone
modifications. How these chromatin modifying protein complexes
are recruited to their target sites is a major question
in molecular genetics.
Several years ago we have developed an assay to monitor
the combinatorial activation of chromatin embedded
myeloid genes by Myb and C/EBP. This assay was subsequently
used to explore the epigenetic mechanisms involved
in the collaboration between both transcription factors.
Cancer Research 89