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

Abstract

BackgroundDown syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood.MethodsWe 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.ResultsWe 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.ConclusionDifferent 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.

Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains

“…Consistent with our observation that MeCP2 is underexpressed in DS brain specimens, other investigators performing mRNA expression survey experiments utilizing RNA isolated from DS fetal fibroblasts and hearts demonstrated that, although a large number of Hsa21 genes were consistently overexpressed, many non-Hsa21 genes were underexpressed, including MeCP2 (50,51). Additionally, Nagarajan et al (52) demonstrated that the MeCP2 protein was underexpressed in several DS frontal cortex samples.…”

Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

“…Although previous reports identified significant differential expression of trisomic genes, our analysis did not. We note that, because most of the amniotic fluid RNA is cell-free, care should be taken when comparing our results to previously published transcriptomic profiles of material that used fetal cells or tissue (12,13,15,16,30,38,39). This discrepancy may also be due to comparison with data derived from mouse models of DS, which are more genetically homogeneous than our human population sample.…”

No Evidence for Mutations that Deregulate GARS–AIRS–GART Protein Levels in Children with Down Syndrome

“…Microarray studies of heart tissue from trisomy-21 fetus with mean gestational age 16.8 weeks when compared to age-matched controls reveals a 3.02-fold over-expression of GARS-AIRS-GART [30]. In Ts65Dn mice that exhibit segmental trisomy for genes on human chromosome 21, only four tissues (cerebral cortex, heart, testis and liver) show the 1.5-fold overexpression rule with regard to gene expression [31].…”