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 p78(MX1) 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. Conclusion: 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.