Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 6
GENETIC AND EPIGENETIC CONTROL OF HEMATOPOIETIC STEM CELLS
PROLIFERATION.
Leonid V. Bystrykh, Alice Gerrits, Leonie M. Kamminga, Ronald van Os, Albertina
Ausema, Ellen Weersing, Bert Dontje, Gerald de Haan.
Department of Cell Biology, Section Stem Cell biology. University Medical Center
Groningen, University of Groningen, 9713 AV Ant.Deusinglaan 1, The Netherlands.
Previously, we identified two major loci controlling HSC behaviour, namely Scp2 at ch11
(55-85 Mb) affecting proliferation, and a locus at ch18 (12-32 Mb) affecting HSC pool size.
Genome-wide microarray-based profiling of gene expressions using mRNA isolated from
murine hematopoietic stem cells was deposited in the www.genenetwork.org database [1].
Having used a set of 30 recombinant BXD inbred lines we were able to map controlling loci
(QTLs) for thousands of transcripts. From a list of 12422 probe sets on the Affymetrix Murine
Genome U74Av2 GeneChip we identified 3615 transcripts with heritable variation in
expression levels. Of these, 399 were highly significantly cis acting (cutoff -10logP 2.93)
and 3216 trans-acting transcripts. Our studies with BXDs suggest that the HSC controlling
locus on ch18 is likely to be regulated by chromatin remodeling genes.
It is known that serial transplantation of mouse HSC causes gradual deterioration of stem cell
function, reminiscent with senescence phenotype. Our microarray analysis of serially
transplanted HSC showed 300 genes to be either up- or downregulated. Comparison of these
data with recently published microarray data, allowed us to identify essential components of
a genomic network operating in HSCs. These include components of PcG and TrxG
epigenetic complexes, which appear to cross talk with Shh, Wnt ant Notch pathways.
Collectively, these genes are largely responsible for maintenance and proliferation of HSC.
Currently we are verifying our network by selective retroviral overexpression of some
essential genes (Ezh2, Msi1h).
Literature
[1] Bystrykh L, Weersing E, Dontje B, Sutton S, Pletcher MT, Wiltshire T, Su AI, Vellenga
E, Wang J, Manly KF, Lu L, Chesler EJ, Alberts R, Jansen RC, Williams RW, Cooke MP, de
Haan G. Uncovering regulatory pathways that affect hematopoietic stem cell function using
'genetical genomics'. Nat Genet. 2005;37(3):225-32.
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