Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21.
BACKGROUND
Down syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood.


METHODS
We used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry.


RESULTS
We found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78MX1 protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR.


CONCLUSIONS
Different subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects.
Li
Chi-Ming
CM
Institute for Cancer Genetics, Columbia University College of Physicians and Surgeons, New York, NY, USA. cl793@columbia.edu
Guo
Meirong
M
Salas
Martha
M
Schupf
Nicole
N
Silverman
Wayne
W
Zigman
Warren B
WB
Husain
Sameera
S
Warburton
Dorothy
D
Thaker
Harshwardhan
H
Tycko
Benjamin
B
D000506:Alopecia Areata / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019731:Carbon-Nitrogen Ligases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D005318:Fetal Heart / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D051026:Phosphoribosylglycinamide Formyltransferase / Q000235:genetics / Q000378:metabolism
D009097:Multienzyme Complexes; D064547:Myxovirus Resistance Proteins; D051026:Phosphoribosylglycinamide Formyltransferase; D019204:GTP-Binding Proteins; D019731:Carbon-Nitrogen Ligases; C494823:GART protein, human