PEBC Report - Programa de Epigenética y Biología del Cáncer

PEBC RESEARCH GROUPS WITH THEIR LEADER BIOGRAPHIES, SCIENTIFIC INTERESTS AND ILLUSTRATIVE PUBLICATIONS
The hematopoietic system is a complex and fascinating
model of cell commitment and differentiation.
Hematopoietic stem cells (HSC) have the potential to generate
all mature blood cell types. To achieve this, HSC and
multipotent progenitors (MMP) develop into more lineagerestricted
cell fates, common lymphoid progenitors (CLP)
and common myeloid progenitors (CMP). CMPs will differentiate
into megakaryocyte/erythrocyte progenitors
(MEPs) and granulocyte/macrophage progenitors
(GMPs), whereas CLPs will differentiate into pro-B and
pro-T cells. Since the stability of every differentiation step
is critical, each transition is tightly regulated at the transcriptional
level through the action of lineage-restricted
transcription factors that induce genes characteristic of
particular cellular states. Importantly, deregulation of particular
transcriptional programs leads to hematological
malignancies.
Surprisingly, very little is known on the potential epigenetic
control of HSC differentiation events to date. Indeed,
the role of chromatin modifying enzymes, such as histone
acetyl transferases (HATs) and histone deacetylases
(HDACs), as well as chromatin remodeling complexes in
the lineage commitment and differentiation of hematopoietic
cells is poorly understood.
The main goals of our laboratory are:
1.To investigate the role of HDACs in the lineage commitment
of hematopoietic cells. Once a progenitor has
chosen to become a particular cell type, it will both upregulate
lineage specific genes, and repress inappropriate
genes characteristic of other cellular lineages.
2.To investigate the role of chromatin remodeling complexes,
such as the SWI/SNF complex, in the lineage
commitment and differentiation of hematopoietic cells.
3.To investigate the potential role of chromatin regulators
in the development of hematological malignancies.
Selected publications
Wang S, Li X, Parra M, Verdin E, Bassel-Duby R, Olson EN.
Control of endothelial cell proliferation and migration by
VEGF signaling to histone deacetylase 7. Proc Natl Acad
Sci U S A. 2008. 105(22):7738-43.
Parra M, Mahmoudi T and Verdin E. Myosin phosphatase
dephosphorylates HDAC7, controls its nucleo-cytoplasmic
shuttling and inhibits apoptosis in thymocytes. Genes and
Development. 2007. 21(6):638-43.
Mahmoudi T, Parra M, Vries R, Kauder S, Verrijzer P, Ott M
and Verdin E. The SWI/SNF Chromatin-Remodeling
Complex is a Cofactor for Tat Transactivation of the HIV
Promoter. Journal of Biological Chemistry. 2006. 281(29):
19960-8.
Mahmoudi T, Parra M, Vries R, Kauder S, Verrijzer P, Ott M
and Verdin E. The SWI/SNF Parra M, Kasler H, McKinsey
TA, Olson EN and Verdin E. Protein kinase D1 phosphorylates
HDAC7 and induces its nuclear export after T-cell
receptor activation. Journal of Biological Chemistry. 2005.
280(14): 13762-70.
Vidal B, Parra M, Jardi M, Saito S, Appella E and Muñoz-
Cánoves P. The alkylating carcinogen N-methyl-N'-nitro-Nnitrosoguanidine
activates the plasminogen activator
inhibitor-1 gene through sequential phosphorylation of p53
by ATM and ATR kinases. Thrombosis and Haemostasis.
2005. 93(3): 584-91.
Parra M. Jardí M. Koziczak M, Nagamine Y and Muñoz-
Cánoves P. p53 phosphorylation at serine 15 is required for
transcriptional induction of the plasminogen activator
inhibitor-1 (PAI-1) gene by the alkylating agent MNNG.
Journal of Biological Chemistry, 2001. 276:36303-10
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