Transcriptome Profiling Uncovers Potential Common Mechanisms in Fetal Trisomies 18 and 21

Abstract

Human trisomies have recently been investigated using transcriptomics approaches to identify the gene expression (GE) signatures characteristic of each of these specific aneuploidy conditions. We hypothesized that the viability of cells with gross genomic imbalances might be associated with the activation of resilience mechanisms that are common to different trisomies and that are reflected by specific shared GE patterns. We report in this article our microarray GE analyses of amniocytes from fetuses with viable trisomy conditions, trisomy 21 or trisomy 18, to detect such common expression signatures. Comparative analysis of significantly differentially expressed genes in trisomies 18 and 21 revealed six dysregulated genes common to both: OTUD5, ADAMTSL1, TADA2A, PPID, PIAS2, and MAPRE2. These genes are involved in ubiquitination, protein folding, cell proliferation, and apoptosis. Pathway-based enrichment analyses demonstrated that both trisomies showed dysregulation of the PI3K/AKT pathway, cell cycle G2/M DNA damage checkpoint regulation, and cell death and survival, as well as inhibition of the upstream regulator TP53. Our data collectively suggest that trisomies 18 and 21 share common functional GE signatures, implying that common mechanisms of resilience might be activated in aneuploid cells to resist large genomic imbalances. To the best of our knowledge, this is the first study to use global GE profiling data to identify potential common mechanisms in fetal trisomies. Studies of other trisomies using transcriptomics and multiomics approaches might further clarify mechanisms activated in trisomy syndromes.

Are there common mechanisms of aneuploidy-related abortion and defects in fetus?

“…Surprisingly, we also found that ubiquitination and histone acetylation was presented in all monosomies. For ubiquitination, few studies have reported that ubiquitination is present in trisomy 18 and trisomy 21 [7,40], which is not consistent with us. No similar studies investigated this pathway in monosomies, and therefore it is di cult for us to discuss with other studies.…”

“…Although theoretically the global effect on the whole transcriptome in various aneuploidies should be very inconsistent because they include different sets of disturbed genes, we found various aneuploidies share some similar phenotypic and molecular characteristics clinically [7][8][9][10]. Thus, there may be some common mechanisms among them, including some of the key biomarkers and pathways to all aneuploidies, could be bene t to early diagnosis and effective treatment of these diseases.…”

“…Thus, one of main strengths of our work was that we did a comprehensive analysis of 24-chromosome (every monosomy and trisomy) to identify potential common mechanisms in all trisomies and monosomies, although increasing evidence have highlighted that there were common mechanisms between chromosomal anomaly [7,13,[26][27][28].…”

“…Some key biomarkers and pathways in aneuploidy have been found by using bioinformatics technologies to integrate and analyze these datasets [13][14][15]. Recent studies indicated that some aneuploidies such as trisomy 18, 21 or trisomy 8, 13, 22, monosomy 45, x have potential common mechanisms [7,13].…”

“…Large genomic imbalance of aneuploidy for gene expression is attributed to both abnormal chromosomelinked gene and genes on other chromosomes. Some evidences have suggested that only few genes on the aneuploid chromosome can reach the theoretical 0.5 or 1.5-fold change, and several euploid genes show disrupted expression pro les [5][6][7]. These evidences indicated that aneuploidy has a global effect on the whole transcriptome.…”