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Gene expression analysis of induced pluripotent stem cells from aneuploid chromosomal syndromes.

Zhang R, Hao L, Wang L, Chen M, Li W, Li R, Yu J, Xiao J, Wu J - BMC Genomics (2013)

Bottom Line: Due to the high mortality associated with aneuploidy, the pathophysiological mechanisms of aneuploidy syndrome remain largely unknown.Our results demonstrate that the extra or missing chromosome has extensive effects on the whole transcriptome.Functional analysis of differentially expressed genes reveals that the genes most affected in aneuploid individuals are related to central nervous system development and tumorigenesis.

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ABSTRACT

Background: Human aneuploidy is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies. Due to the high mortality associated with aneuploidy, the pathophysiological mechanisms of aneuploidy syndrome remain largely unknown. Previous studies focused mostly on whether dosage compensation occurs, and the next generation transcriptomics sequencing technology RNA-seq is expected to eventually uncover the mechanisms of gene expression regulation and the related pathological phenotypes in human aneuploidy.

Results: Using next generation transcriptomics sequencing technology RNA-seq, we profiled the transcriptomes of four human aneuploid induced pluripotent stem cell (iPSC) lines generated from monosomy × (Turner syndrome), trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome), and partial trisomy 11:22 (Emanuel syndrome) as well as two umbilical cord matrix iPSC lines as euploid controls to examine how phenotypic abnormalities develop with aberrant karyotype. A total of 466 M (50-bp) reads were obtained from the six iPSC lines, and over 13,000 mRNAs were identified by gene annotation. Global analysis of gene expression profiles and functional analysis of differentially expressed (DE) genes were implemented. Over 5000 DE genes are determined between aneuploidy and euploid iPSCs respectively while 9 KEGG pathways are overlapped enriched in four aneuploidy samples.

Conclusions: Our results demonstrate that the extra or missing chromosome has extensive effects on the whole transcriptome. Functional analysis of differentially expressed genes reveals that the genes most affected in aneuploid individuals are related to central nervous system development and tumorigenesis.

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DE genes amount between euploid and aneuploid iPSCs. The threshold is P value≤0.05, and Q value≤0.05. A. DE genes are classified into up- or down-regulated genes with fold change>1.5. B. DE genes are calculated with different cut-offs of fold change (FC).
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Figure 3: DE genes amount between euploid and aneuploid iPSCs. The threshold is P value≤0.05, and Q value≤0.05. A. DE genes are classified into up- or down-regulated genes with fold change>1.5. B. DE genes are calculated with different cut-offs of fold change (FC).

Mentions: We considered a gene to be significantly DE between two iPSC lines if P-values and Q-values of DEGseq results were both less than 0.05. If one gene is both up-regulated or both down-regulated in UMC1 and UMC6 compared to one aneuploid cell line, it is classified as a "both" up-regulated or down-regulated gene. We find that more than 60% of up- or down-regulated genes in aneuploid clones are "both" up- or down-regulated genes, confirming the differences between aneuploid and euploid iPSC clones. The numbers of up- and down-regulated genes in each aneuploid line were generally similar. There were more up-regulated genes in trisomy 8 and trisomy 13, whereas there were more down-regulated genes in trisomy 22 and monosomy × (Figure 3A, Additional File 3). Compared to previous transcriptome analysis of trisomy 13 and trisomy 8 with DNA microarray [19,20], RNA-seq data detects more signal of expressed genes. Thus, microarray results may not be able to reliably identify differential expressed genes with small fold change [27], while RNA-seq technology perform excellently in measuring gene expression levels with enough depth and sensitivity [28].


Gene expression analysis of induced pluripotent stem cells from aneuploid chromosomal syndromes.

Zhang R, Hao L, Wang L, Chen M, Li W, Li R, Yu J, Xiao J, Wu J - BMC Genomics (2013)

DE genes amount between euploid and aneuploid iPSCs. The threshold is P value≤0.05, and Q value≤0.05. A. DE genes are classified into up- or down-regulated genes with fold change>1.5. B. DE genes are calculated with different cut-offs of fold change (FC).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852284&req=5

Figure 3: DE genes amount between euploid and aneuploid iPSCs. The threshold is P value≤0.05, and Q value≤0.05. A. DE genes are classified into up- or down-regulated genes with fold change>1.5. B. DE genes are calculated with different cut-offs of fold change (FC).
Mentions: We considered a gene to be significantly DE between two iPSC lines if P-values and Q-values of DEGseq results were both less than 0.05. If one gene is both up-regulated or both down-regulated in UMC1 and UMC6 compared to one aneuploid cell line, it is classified as a "both" up-regulated or down-regulated gene. We find that more than 60% of up- or down-regulated genes in aneuploid clones are "both" up- or down-regulated genes, confirming the differences between aneuploid and euploid iPSC clones. The numbers of up- and down-regulated genes in each aneuploid line were generally similar. There were more up-regulated genes in trisomy 8 and trisomy 13, whereas there were more down-regulated genes in trisomy 22 and monosomy × (Figure 3A, Additional File 3). Compared to previous transcriptome analysis of trisomy 13 and trisomy 8 with DNA microarray [19,20], RNA-seq data detects more signal of expressed genes. Thus, microarray results may not be able to reliably identify differential expressed genes with small fold change [27], while RNA-seq technology perform excellently in measuring gene expression levels with enough depth and sensitivity [28].

Bottom Line: Due to the high mortality associated with aneuploidy, the pathophysiological mechanisms of aneuploidy syndrome remain largely unknown.Our results demonstrate that the extra or missing chromosome has extensive effects on the whole transcriptome.Functional analysis of differentially expressed genes reveals that the genes most affected in aneuploid individuals are related to central nervous system development and tumorigenesis.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Human aneuploidy is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies. Due to the high mortality associated with aneuploidy, the pathophysiological mechanisms of aneuploidy syndrome remain largely unknown. Previous studies focused mostly on whether dosage compensation occurs, and the next generation transcriptomics sequencing technology RNA-seq is expected to eventually uncover the mechanisms of gene expression regulation and the related pathological phenotypes in human aneuploidy.

Results: Using next generation transcriptomics sequencing technology RNA-seq, we profiled the transcriptomes of four human aneuploid induced pluripotent stem cell (iPSC) lines generated from monosomy × (Turner syndrome), trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome), and partial trisomy 11:22 (Emanuel syndrome) as well as two umbilical cord matrix iPSC lines as euploid controls to examine how phenotypic abnormalities develop with aberrant karyotype. A total of 466 M (50-bp) reads were obtained from the six iPSC lines, and over 13,000 mRNAs were identified by gene annotation. Global analysis of gene expression profiles and functional analysis of differentially expressed (DE) genes were implemented. Over 5000 DE genes are determined between aneuploidy and euploid iPSCs respectively while 9 KEGG pathways are overlapped enriched in four aneuploidy samples.

Conclusions: Our results demonstrate that the extra or missing chromosome has extensive effects on the whole transcriptome. Functional analysis of differentially expressed genes reveals that the genes most affected in aneuploid individuals are related to central nervous system development and tumorigenesis.

Show MeSH
Related in: MedlinePlus