Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21

• Main Authors: Zigman Warren B, Silverman Wayne, Schupf Nicole, Salas Martha, Guo Meirong, Li Chi-Ming, Husain Sameera, Warburton Dorothy, Thaker Harshwardhan, Tycko Benjamin
• Format: Article
• Language: English
• Published: BMC 2006-03-01
• Series: BMC Medical Genetics
• Online Access: http://www.biomedcentral.com/1471-2350/7/24

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 <it>MX1 </it>was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. <it>MX1 </it>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^MX1protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene <it>GART </it>(mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR.</p> <p>Conclusion</p> <p>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.</p>