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FOG-1, a transcriptional regulator within the haematopoietic system

Versavel, Aude. FOG-1, a transcriptional regulator within the haematopoietic system. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10684

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Abstract

Friend of GATA-1 (FOG-1) is a member of the friend of GATA (FOG)
family of proteins, which consists of large multitype zinc finger cofactors that
bind to the amino zinc finger of GATA transcription factors and modulate their
activity. FOG-1 also interacts with the C-terminal binding protein (CtBP),
mainly known as a corepressor and the nucleosome remodelling and histone
deacetylase repressive (NuRD) complex ; thus, integrating FOG-1 into the
transcription factor and chromatin modifier networks. Remarkably, the protein
activates or represses gene transcription by facilitating binding of GATA
factors to DNA, recruiting chromatin remodelling complexes, or by stabilizing
tissue-specific chromatin loops. Physical interaction between FOG and GATA
proteins in vivo is essential for the development of a broad array of tissues,
reflecting the overlapping expression patterns of these factors. Notably, within
the haematopoietic system, FOG-1 is absent in most of the myeloid lineages ;
it is expressed at high level in multipotent progenitors, erythroid and
megakaryocytic cells, low level in lymphoid and haematopoietic stem cells.
The cofactor is essential for differentiation of the erythroid and
megakaryocytic lineages, notably by interacting with GATA-1. FOG-1 also
plays a role in the T-lineage by repressing GATA-3 dependent induction of
Th2 development. Interestingly, overexpression of FOG-1 in avian
eosinophils, which do not normally express FOG-1, reprograms these
differentiated cells into multipotent cells. To study FOG-1 in mammals, we
used a novel transgenic mouse model strategy which we had designed to
generate mice with conditional overexpression of FOG-1. Our work with
enforced expression of FOG-1 in the whole murine haematopoietic system led
to a reduction in the number of circulating eosinophils, confirming and
extending to mammals the previously reported role of FOG-1 in repressing
this lineage development. Strikingly, we have identified the expression of
FOG-1 in early B lymphocytes, but not in late developmental stages such as
mature B cells and plasma cells. Moreover, FOG-1 function had never been
described in the B-lineage, where GATA factors are not expressed. Therefore,
we were intrigued by both the regulated expression of FOG-1 during B cell
development and its molecular mechanism of action in the absence of GATA
factors. Thus, we generated transgenic mice in which FOG-1 expression was
enforced at a physiologically relevant level in the B lymphoid system : in
mature B cells and from early B cell stages. We found that sustained FOG-1
expression in mature and late B cells did not affect their development or
function, contrary to our expected hypothesis. Although the mice
overexpressing FOG-1 from early B cell lineages showed only a weak
phenotype, we extensively studied FOG-1 partners in early B cell stages.
Indeed, describing FOG-1 molecular mechanism of action in the absence of
GATA factors is a question that warrant further investigation. We notably
found FOG-1 in complex with Ikaros, a transcription factor well described as
crucial for B cell development. The cofactor was also found associated to the
CtBP and NuRD epigenetic complexes in B cell lines.
Advisors:Matthias, Patrick D.
Committee Members:Rolink, Antonius G.
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI > Epigenetics > Transcriptional and epigenetic networks and function of histone deacetylases in mammals (Matthias)
Item Type:Thesis
Thesis no:10684
Bibsysno:Link to catalogue
Number of Pages:176 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:55
Deposited On:05 Mar 2014 14:33

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