Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'.
We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.
Bystrykh
Leonid
L
Department of Stem Cell Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Weersing
Ellen
E
Dontje
Bert
B
Sutton
Sue
S
Pletcher
Mathew T
MT
Wiltshire
Tim
T
Su
Andrew I
AI
Vellenga
Edo
E
Wang
Jintao
J
Manly
Kenneth F
KF
Lu
Lu
L
Chesler
Elissa J
EJ
Alberts
Rudi
R
Jansen
Ritsert C
RC
Williams
Robert W
RW
Cooke
Michael P
MP
de Haan
Gerald
G
D002352:Carrier Proteins / Q000235:genetics; D015894:Genome, Human; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008969:Molecular Sequence Data; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics
D002352:Carrier Proteins; D012333:RNA, Messenger; C072087:sterol carrier proteins