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Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression.

Grinchuk OV, Motakis E, Kuznetsov VA - BMC Genomics (2010)

Bottom Line: Survival analysis of a group of 410 breast cancer patients revealed significant survival-associated individual genes and gene pairs in the TNFAIP1/POLDIP2 CSAGA.Moreover, several of the gene pairs associated with survival, demonstrated synergistic effects.We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module associated with amplification of the genomic region on 17q11.2 and correlated with expression ERBB2 amplicon core genes in breast cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute, 30 Biopolis Str, Singapore. olegg@bii.a-star.edu.sg

ABSTRACT

Background: A sense-antisense gene pair (SAGP) is a gene pair where two oppositely transcribed genes share a common nucleotide sequence region. In eukaryotic genomes, SAGPs can be organized in complex sense-antisense architectures (CSAGAs) in which at least one sense gene shares loci with two or more antisense partners. As shown in several case studies, SAGPs may be involved in cancers, neurological diseases and complex syndromes. However, CSAGAs have not yet been characterized in the context of human disease or cancer.

Results: We characterize five genes (TMEM97, IFT20, TNFAIP1, POLDIP2 and TMEM199) organized in a CSAGA on 17q11.2 (we term this the TNFAIP1/POLDIP2 CSAGA) and demonstrate their strong and reproducible co-regulatory transcription pattern in breast cancer tumours. Genes of the TNFAIP1/POLDIP2 CSAGA are located inside the smallest region of recurrent amplification on 17q11.2 and their expression profile correlates with the DNA copy number of the region. Survival analysis of a group of 410 breast cancer patients revealed significant survival-associated individual genes and gene pairs in the TNFAIP1/POLDIP2 CSAGA. Moreover, several of the gene pairs associated with survival, demonstrated synergistic effects. Expression of genes-members of the TNFAIP1/POLDIP2 CSAGA also strongly correlated with expression of genes of ERBB2 core region of recurrent amplification on 17q12. We clearly demonstrate that the observed co-regulatory transcription profile of the TNFAIP1/POLDIP2 CSAGA is maintained not only by a DNA amplification mechanism, but also by chromatin remodelling and local transcription activation.

Conclusion: We have identified a novel TNFAIP1/POLDIP2 CSAGA and characterized its co-regulatory transcription profile in cancerous breast tissues. We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module associated with amplification of the genomic region on 17q11.2 and correlated with expression ERBB2 amplicon core genes in breast cancer. Co-expression pattern of this module correlates with histological grades and a poor prognosis in breast cancer when over-expressed. TNFAIP1/POLDIP2 CSAGA maps the risks of breast cancer relapse onto the complex genomic locus on 17q11.2.

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TNFAIP1/POLDIP2 complex sense antisense architecture mapped onto the genome (UCSC genomic browser). A - TNFAIP1/POLDIP SAGP (red arrows) and TMEM97/IFT20 SAGP (two next closest blue arrows on the left) with seven other genes included in the analysis (blue arrows). B - TNFAIP1/POLDIP2 complex cis-sense antisense architecture (red box) with different tracks. Small green solid boxes represent CpG islands, and green transparent boxes represent regions of enrichment of potential miRNA regulatory target sites. ChIP-Seq tracks represent regions of DNA binding by STAT1 (human cervical cancer HeLaS3 cell line [42]), ChIP-PET-defined histone trimethylations H3K4me3 and H3K27me3 (promyelocytic leukemia cell line HL60 [40]) and ChIP-seq-defined RNA polymerase II binding (breast cancer cell line MCF7 [44]). Black arrows at the bottom indicate the direct evidence of transcription activation of the TNFAIP1/POLDIP2 CSAGA in the breast cancer cell line. The GIS ChiP-PET track shows H3K4me3 and H3K27me3 regions mapped on the human genome (embryonic stem cell line hES3 [41]).
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Figure 2: TNFAIP1/POLDIP2 complex sense antisense architecture mapped onto the genome (UCSC genomic browser). A - TNFAIP1/POLDIP SAGP (red arrows) and TMEM97/IFT20 SAGP (two next closest blue arrows on the left) with seven other genes included in the analysis (blue arrows). B - TNFAIP1/POLDIP2 complex cis-sense antisense architecture (red box) with different tracks. Small green solid boxes represent CpG islands, and green transparent boxes represent regions of enrichment of potential miRNA regulatory target sites. ChIP-Seq tracks represent regions of DNA binding by STAT1 (human cervical cancer HeLaS3 cell line [42]), ChIP-PET-defined histone trimethylations H3K4me3 and H3K27me3 (promyelocytic leukemia cell line HL60 [40]) and ChIP-seq-defined RNA polymerase II binding (breast cancer cell line MCF7 [44]). Black arrows at the bottom indicate the direct evidence of transcription activation of the TNFAIP1/POLDIP2 CSAGA in the breast cancer cell line. The GIS ChiP-PET track shows H3K4me3 and H3K27me3 regions mapped on the human genome (embryonic stem cell line hES3 [41]).

Mentions: Using the high-confidence Affymetrix Chip U133 A&B probesets presented in the APMA database [22], http://apma.bii.a-star.edu.sg/, we selected 156 SAGPs located on chromosome 17 with reliable RefSeq support (those IDs with NM prefixes) for each member of each pair. Each of the genes in these SAGPs was supported by at least 1 Affymetrix Chip U133 A&B probesets. We focused on chromosome 17 because many regions of that chromosome are actively involved in recurrent amplifications during breast cancer development (including the ERBB2 amplicon). Using mRNA expression data from the Uppsala and Stockholm cohorts, we calculated Pearson correlations for each pair and identified high-confidence correlated pairs of probesets (α = 1%) representing twelve SAGPs. Among these positively- and highly-correlated SAGPs, two convergent SA gene pairs (the TNFAIP1/POLDIP2 SAGP and the IFT20/TMEM97 SAGP) attracted our attention (Figure 2B) because TNFAIP1 and IFT20 also have a common SA overlapping region. Thus, these two SAGPs were in fact the parts of the same complex CSAGA. Our further work was focused on the detailed characterization of this CSAGA.


Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression.

Grinchuk OV, Motakis E, Kuznetsov VA - BMC Genomics (2010)

TNFAIP1/POLDIP2 complex sense antisense architecture mapped onto the genome (UCSC genomic browser). A - TNFAIP1/POLDIP SAGP (red arrows) and TMEM97/IFT20 SAGP (two next closest blue arrows on the left) with seven other genes included in the analysis (blue arrows). B - TNFAIP1/POLDIP2 complex cis-sense antisense architecture (red box) with different tracks. Small green solid boxes represent CpG islands, and green transparent boxes represent regions of enrichment of potential miRNA regulatory target sites. ChIP-Seq tracks represent regions of DNA binding by STAT1 (human cervical cancer HeLaS3 cell line [42]), ChIP-PET-defined histone trimethylations H3K4me3 and H3K27me3 (promyelocytic leukemia cell line HL60 [40]) and ChIP-seq-defined RNA polymerase II binding (breast cancer cell line MCF7 [44]). Black arrows at the bottom indicate the direct evidence of transcription activation of the TNFAIP1/POLDIP2 CSAGA in the breast cancer cell line. The GIS ChiP-PET track shows H3K4me3 and H3K27me3 regions mapped on the human genome (embryonic stem cell line hES3 [41]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822537&req=5

Figure 2: TNFAIP1/POLDIP2 complex sense antisense architecture mapped onto the genome (UCSC genomic browser). A - TNFAIP1/POLDIP SAGP (red arrows) and TMEM97/IFT20 SAGP (two next closest blue arrows on the left) with seven other genes included in the analysis (blue arrows). B - TNFAIP1/POLDIP2 complex cis-sense antisense architecture (red box) with different tracks. Small green solid boxes represent CpG islands, and green transparent boxes represent regions of enrichment of potential miRNA regulatory target sites. ChIP-Seq tracks represent regions of DNA binding by STAT1 (human cervical cancer HeLaS3 cell line [42]), ChIP-PET-defined histone trimethylations H3K4me3 and H3K27me3 (promyelocytic leukemia cell line HL60 [40]) and ChIP-seq-defined RNA polymerase II binding (breast cancer cell line MCF7 [44]). Black arrows at the bottom indicate the direct evidence of transcription activation of the TNFAIP1/POLDIP2 CSAGA in the breast cancer cell line. The GIS ChiP-PET track shows H3K4me3 and H3K27me3 regions mapped on the human genome (embryonic stem cell line hES3 [41]).
Mentions: Using the high-confidence Affymetrix Chip U133 A&B probesets presented in the APMA database [22], http://apma.bii.a-star.edu.sg/, we selected 156 SAGPs located on chromosome 17 with reliable RefSeq support (those IDs with NM prefixes) for each member of each pair. Each of the genes in these SAGPs was supported by at least 1 Affymetrix Chip U133 A&B probesets. We focused on chromosome 17 because many regions of that chromosome are actively involved in recurrent amplifications during breast cancer development (including the ERBB2 amplicon). Using mRNA expression data from the Uppsala and Stockholm cohorts, we calculated Pearson correlations for each pair and identified high-confidence correlated pairs of probesets (α = 1%) representing twelve SAGPs. Among these positively- and highly-correlated SAGPs, two convergent SA gene pairs (the TNFAIP1/POLDIP2 SAGP and the IFT20/TMEM97 SAGP) attracted our attention (Figure 2B) because TNFAIP1 and IFT20 also have a common SA overlapping region. Thus, these two SAGPs were in fact the parts of the same complex CSAGA. Our further work was focused on the detailed characterization of this CSAGA.

Bottom Line: Survival analysis of a group of 410 breast cancer patients revealed significant survival-associated individual genes and gene pairs in the TNFAIP1/POLDIP2 CSAGA.Moreover, several of the gene pairs associated with survival, demonstrated synergistic effects.We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module associated with amplification of the genomic region on 17q11.2 and correlated with expression ERBB2 amplicon core genes in breast cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute, 30 Biopolis Str, Singapore. olegg@bii.a-star.edu.sg

ABSTRACT

Background: A sense-antisense gene pair (SAGP) is a gene pair where two oppositely transcribed genes share a common nucleotide sequence region. In eukaryotic genomes, SAGPs can be organized in complex sense-antisense architectures (CSAGAs) in which at least one sense gene shares loci with two or more antisense partners. As shown in several case studies, SAGPs may be involved in cancers, neurological diseases and complex syndromes. However, CSAGAs have not yet been characterized in the context of human disease or cancer.

Results: We characterize five genes (TMEM97, IFT20, TNFAIP1, POLDIP2 and TMEM199) organized in a CSAGA on 17q11.2 (we term this the TNFAIP1/POLDIP2 CSAGA) and demonstrate their strong and reproducible co-regulatory transcription pattern in breast cancer tumours. Genes of the TNFAIP1/POLDIP2 CSAGA are located inside the smallest region of recurrent amplification on 17q11.2 and their expression profile correlates with the DNA copy number of the region. Survival analysis of a group of 410 breast cancer patients revealed significant survival-associated individual genes and gene pairs in the TNFAIP1/POLDIP2 CSAGA. Moreover, several of the gene pairs associated with survival, demonstrated synergistic effects. Expression of genes-members of the TNFAIP1/POLDIP2 CSAGA also strongly correlated with expression of genes of ERBB2 core region of recurrent amplification on 17q12. We clearly demonstrate that the observed co-regulatory transcription profile of the TNFAIP1/POLDIP2 CSAGA is maintained not only by a DNA amplification mechanism, but also by chromatin remodelling and local transcription activation.

Conclusion: We have identified a novel TNFAIP1/POLDIP2 CSAGA and characterized its co-regulatory transcription profile in cancerous breast tissues. We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module associated with amplification of the genomic region on 17q11.2 and correlated with expression ERBB2 amplicon core genes in breast cancer. Co-expression pattern of this module correlates with histological grades and a poor prognosis in breast cancer when over-expressed. TNFAIP1/POLDIP2 CSAGA maps the risks of breast cancer relapse onto the complex genomic locus on 17q11.2.

Show MeSH
Related in: MedlinePlus