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

Chi Ming Li, Meirong Guo, Martha Salas, Nicole Schupf, Wayne Silverman, Warren B. Zigman, Sameera Husain, Dorothy Warburton, Harshwardhan Thaker, Benjamin Tycko

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Background: Down syndrome (DS) is caused by trisomy 21 (+2 1), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood. Methods: We used oligonuc leotide 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 NIXI was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. NIXI 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 p78MXI 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 +2 1, 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.

Original languageEnglish (US)
Article number24
JournalBMC Medical Genetics
Volume7
DOIs
StatePublished - Mar 15 2006
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Li, C. M., Guo, M., Salas, M., Schupf, N., Silverman, W., Zigman, W. B., Husain, S., Warburton, D., Thaker, H., & Tycko, B. (2006). Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal with trisomy 21. BMC Medical Genetics, 7, [24]. https://doi.org/10.1186/1471-2350-7-24