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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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Gene regulation distribution on each chromosome. Percentages of DE genes out of all expressed genes on each chromosome are shown as up-regulated part (A) and down-regulated part (B). On y-axis, breaks in scale are introduced because of the high percentage of chromosome 10 in T8 and chromosome 3 in T22.
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Figure 5: Gene regulation distribution on each chromosome. Percentages of DE genes out of all expressed genes on each chromosome are shown as up-regulated part (A) and down-regulated part (B). On y-axis, breaks in scale are introduced because of the high percentage of chromosome 10 in T8 and chromosome 3 in T22.

Mentions: We examined the up or down regulation of all expressed genes on each chromosome, and we found that transcriptome regulation is ubiquitous on all chromosomes not just on the extra chromosome or single remaining chromosome (Figure 5). In the four aneuploid cell lines, 8-20% of genes on each chromosome were up regulated, whereas the percentage of down-regulated genes varied between 5% and 24%, a slightly wider range than for up regulation. The exceptions were chromosome 19 in all four aneuploid lines, chromosome 3 in trisomy 22, and chromosome 10 in trisomy 8. The exceptional performance of gene expression regulation on chromosome 19 was very similar among the four aneuploid samples, with less than 10% of genes up-regulated and more than 20% down-regulated (as high as 35% in monosomy X). For chromosome 3 in trisomy 22, a very low percentage (only 0.7%) of genes were up regulated, whereas more than 70% of genes on the same chromosome were down regulated. A similar situation occurred on chromosome 10 in trisomy 8, with only 2.9% genes down regulated and 43.3% up regulated. Notably, the ratio of down-regulated genes on each chromosome of monosomy × is much higher than those on other three aneuploid cell lines, which may be caused by the loss of an × chromosome.


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)

Gene regulation distribution on each chromosome. Percentages of DE genes out of all expressed genes on each chromosome are shown as up-regulated part (A) and down-regulated part (B). On y-axis, breaks in scale are introduced because of the high percentage of chromosome 10 in T8 and chromosome 3 in T22.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Gene regulation distribution on each chromosome. Percentages of DE genes out of all expressed genes on each chromosome are shown as up-regulated part (A) and down-regulated part (B). On y-axis, breaks in scale are introduced because of the high percentage of chromosome 10 in T8 and chromosome 3 in T22.
Mentions: We examined the up or down regulation of all expressed genes on each chromosome, and we found that transcriptome regulation is ubiquitous on all chromosomes not just on the extra chromosome or single remaining chromosome (Figure 5). In the four aneuploid cell lines, 8-20% of genes on each chromosome were up regulated, whereas the percentage of down-regulated genes varied between 5% and 24%, a slightly wider range than for up regulation. The exceptions were chromosome 19 in all four aneuploid lines, chromosome 3 in trisomy 22, and chromosome 10 in trisomy 8. The exceptional performance of gene expression regulation on chromosome 19 was very similar among the four aneuploid samples, with less than 10% of genes up-regulated and more than 20% down-regulated (as high as 35% in monosomy X). For chromosome 3 in trisomy 22, a very low percentage (only 0.7%) of genes were up regulated, whereas more than 70% of genes on the same chromosome were down regulated. A similar situation occurred on chromosome 10 in trisomy 8, with only 2.9% genes down regulated and 43.3% up regulated. Notably, the ratio of down-regulated genes on each chromosome of monosomy × is much higher than those on other three aneuploid cell lines, which may be caused by the loss of an × chromosome.

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