Research article
Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21
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* Corresponding author: Benjamin Tycko bt12@columbia.edu
1 Institute for Cancer Genetics, Columbia University College of Physicians and Surgeons, New York, NY, USA
2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY, USA
3 Gertrude H. Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
4 Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, USA
5 Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA
6 Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, NY, USA
BMC Medical Genetics 2006, 7:24 doi:10.1186/1471-2350-7-24
Published: 15 March 2006Abstract
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.
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.