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Genes associated with the cis-regulatory functions of intragenic LINE-1 elements.

Wanichnopparat W, Suwanwongse K, Pin-On P, Aporntewan C, Mutirangura A - BMC Genomics (2013)

Bottom Line: After a permutation based statistical analysis and a multiple hypothesis testing, 73 genes were found to induce significant regulatory changes (upregulation and/or downregulation) in genes with L1s.In detail, 5 genes were found to induce both the upregulation and downregulation of genes with L1s, whereas 27 and 37 genes induced the downregulation and upregulation, respectively, of genes with L1s.Moreover, the siRNA-regulating genes containing L1s possess a variety of molecular functions, are responsible for many cellular phenotypes and are associated with a number of diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

ABSTRACT

Background: Thousands of intragenic long interspersed element 1 sequences (LINE-1 elements or L1s) reside within genes. These intragenic L1 sequences are conserved and regulate the expression of their host genes. When L1 methylation is decreased, either through chemical induction or in cancer, the intragenic L1 transcription is increased. The resulting L1 mRNAs form RISC complexes with pre-mRNA to degrade the complementary mRNA. In this study, we screened for genes that are involved in intragenic L1 regulation networks.

Results: Genes containing L1s were obtained from L1Base (http://l1base.molgen.mpg.de). The expression profiles of 205 genes in 516 gene knockdown experiments were obtained from the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo). The expression levels of the genes with and without L1s were compared using Pearson's chi-squared test. After a permutation based statistical analysis and a multiple hypothesis testing, 73 genes were found to induce significant regulatory changes (upregulation and/or downregulation) in genes with L1s. In detail, 5 genes were found to induce both the upregulation and downregulation of genes with L1s, whereas 27 and 37 genes induced the downregulation and upregulation, respectively, of genes with L1s. These regulations sometimes differed depending on the cell type and the orientation of the intragenic L1s. Moreover, the siRNA-regulating genes containing L1s possess a variety of molecular functions, are responsible for many cellular phenotypes and are associated with a number of diseases.

Conclusions: Cells use intragenic L1s as cis-regulatory elements within gene bodies to modulate gene expression. There may be several mechanisms by which L1s mediate gene expression. Intragenic L1s may be involved in the regulation of several biological processes, including DNA damage and repair, inflammation, immune function, embryogenesis, cell differentiation, cellular response to external stimuli and hormonal responses. Furthermore, in addition to cancer, intragenic L1s may alter gene expression in a variety of diseases and abnormalities.

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The CU-DREAM extension program. (A) A flow chart illustrating how the microarray data were processed. First, the microarray data for the fields of interest were collected and prepared. The program then computed the status of each gene (upregulated or downregulated) using Student’s t-test. Subsequently, the assessed genes were compared with a list of genes containing intragenic L1s. The results showed the associations between the gene regulation status and the presence of an L1 sequence in terms of ORs and p-values. (B) A table indicating the intersection between each experimental result and the genes containing intragenic L1s. These intersections are referred to as groups A through D. Group A includes the genes that are upregulated or downregulated and contain intragenic L1s. Group B includes the genes that are not upregulated or downregulated but contain intragenic L1s. Group C includes the genes that are upregulated or downregulated but do not contain intragenic L1s. Group D includes the remaining genes, which are not upregulated or downregulated and do not contain intragenic L1s.
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Figure 1: The CU-DREAM extension program. (A) A flow chart illustrating how the microarray data were processed. First, the microarray data for the fields of interest were collected and prepared. The program then computed the status of each gene (upregulated or downregulated) using Student’s t-test. Subsequently, the assessed genes were compared with a list of genes containing intragenic L1s. The results showed the associations between the gene regulation status and the presence of an L1 sequence in terms of ORs and p-values. (B) A table indicating the intersection between each experimental result and the genes containing intragenic L1s. These intersections are referred to as groups A through D. Group A includes the genes that are upregulated or downregulated and contain intragenic L1s. Group B includes the genes that are not upregulated or downregulated but contain intragenic L1s. Group C includes the genes that are upregulated or downregulated but do not contain intragenic L1s. Group D includes the remaining genes, which are not upregulated or downregulated and do not contain intragenic L1s.

Mentions: First, the mRNA levels of the experimental and control samples were evaluated. Using the prepared templates of the microarrays, series matrix files and platforms, Student’s t-test was performed for each gene to compare the means of the control and experimental groups of the examined experiments. Each gene was then determined to be downregulated or upregulated based on the obtained p-value. Subsequently, the distributions of upregulated and downregulated genes were evaluated using Pearson’s chi-squared test to determine whether the distributions were dependent on the presence of an intragenic L1. Genes were classified into four groups, A through D. The significant genes with intragenic L1s that were downregulated or upregulated were included in group A. The significant genes without intragenic L1s were included in group B, whereas the non-significant genes with intragenic L1s were included in group C. The remaining genes (non-significant genes without L1s) were included in group D. The values of odds ratio (OR), p-values, and lower and upper 95% confidence interval (CI) of the genes in groups A through D were displayed in an MS Excel format. All of the statistical analyses were performed using extensions in the CU-DREAM software (http://pioneer.netserv.chula.ac.th/~achatcha/cu-dream/) [24] (Figure 1).


Genes associated with the cis-regulatory functions of intragenic LINE-1 elements.

Wanichnopparat W, Suwanwongse K, Pin-On P, Aporntewan C, Mutirangura A - BMC Genomics (2013)

The CU-DREAM extension program. (A) A flow chart illustrating how the microarray data were processed. First, the microarray data for the fields of interest were collected and prepared. The program then computed the status of each gene (upregulated or downregulated) using Student’s t-test. Subsequently, the assessed genes were compared with a list of genes containing intragenic L1s. The results showed the associations between the gene regulation status and the presence of an L1 sequence in terms of ORs and p-values. (B) A table indicating the intersection between each experimental result and the genes containing intragenic L1s. These intersections are referred to as groups A through D. Group A includes the genes that are upregulated or downregulated and contain intragenic L1s. Group B includes the genes that are not upregulated or downregulated but contain intragenic L1s. Group C includes the genes that are upregulated or downregulated but do not contain intragenic L1s. Group D includes the remaining genes, which are not upregulated or downregulated and do not contain intragenic L1s.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643820&req=5

Figure 1: The CU-DREAM extension program. (A) A flow chart illustrating how the microarray data were processed. First, the microarray data for the fields of interest were collected and prepared. The program then computed the status of each gene (upregulated or downregulated) using Student’s t-test. Subsequently, the assessed genes were compared with a list of genes containing intragenic L1s. The results showed the associations between the gene regulation status and the presence of an L1 sequence in terms of ORs and p-values. (B) A table indicating the intersection between each experimental result and the genes containing intragenic L1s. These intersections are referred to as groups A through D. Group A includes the genes that are upregulated or downregulated and contain intragenic L1s. Group B includes the genes that are not upregulated or downregulated but contain intragenic L1s. Group C includes the genes that are upregulated or downregulated but do not contain intragenic L1s. Group D includes the remaining genes, which are not upregulated or downregulated and do not contain intragenic L1s.
Mentions: First, the mRNA levels of the experimental and control samples were evaluated. Using the prepared templates of the microarrays, series matrix files and platforms, Student’s t-test was performed for each gene to compare the means of the control and experimental groups of the examined experiments. Each gene was then determined to be downregulated or upregulated based on the obtained p-value. Subsequently, the distributions of upregulated and downregulated genes were evaluated using Pearson’s chi-squared test to determine whether the distributions were dependent on the presence of an intragenic L1. Genes were classified into four groups, A through D. The significant genes with intragenic L1s that were downregulated or upregulated were included in group A. The significant genes without intragenic L1s were included in group B, whereas the non-significant genes with intragenic L1s were included in group C. The remaining genes (non-significant genes without L1s) were included in group D. The values of odds ratio (OR), p-values, and lower and upper 95% confidence interval (CI) of the genes in groups A through D were displayed in an MS Excel format. All of the statistical analyses were performed using extensions in the CU-DREAM software (http://pioneer.netserv.chula.ac.th/~achatcha/cu-dream/) [24] (Figure 1).

Bottom Line: After a permutation based statistical analysis and a multiple hypothesis testing, 73 genes were found to induce significant regulatory changes (upregulation and/or downregulation) in genes with L1s.In detail, 5 genes were found to induce both the upregulation and downregulation of genes with L1s, whereas 27 and 37 genes induced the downregulation and upregulation, respectively, of genes with L1s.Moreover, the siRNA-regulating genes containing L1s possess a variety of molecular functions, are responsible for many cellular phenotypes and are associated with a number of diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

ABSTRACT

Background: Thousands of intragenic long interspersed element 1 sequences (LINE-1 elements or L1s) reside within genes. These intragenic L1 sequences are conserved and regulate the expression of their host genes. When L1 methylation is decreased, either through chemical induction or in cancer, the intragenic L1 transcription is increased. The resulting L1 mRNAs form RISC complexes with pre-mRNA to degrade the complementary mRNA. In this study, we screened for genes that are involved in intragenic L1 regulation networks.

Results: Genes containing L1s were obtained from L1Base (http://l1base.molgen.mpg.de). The expression profiles of 205 genes in 516 gene knockdown experiments were obtained from the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo). The expression levels of the genes with and without L1s were compared using Pearson's chi-squared test. After a permutation based statistical analysis and a multiple hypothesis testing, 73 genes were found to induce significant regulatory changes (upregulation and/or downregulation) in genes with L1s. In detail, 5 genes were found to induce both the upregulation and downregulation of genes with L1s, whereas 27 and 37 genes induced the downregulation and upregulation, respectively, of genes with L1s. These regulations sometimes differed depending on the cell type and the orientation of the intragenic L1s. Moreover, the siRNA-regulating genes containing L1s possess a variety of molecular functions, are responsible for many cellular phenotypes and are associated with a number of diseases.

Conclusions: Cells use intragenic L1s as cis-regulatory elements within gene bodies to modulate gene expression. There may be several mechanisms by which L1s mediate gene expression. Intragenic L1s may be involved in the regulation of several biological processes, including DNA damage and repair, inflammation, immune function, embryogenesis, cell differentiation, cellular response to external stimuli and hormonal responses. Furthermore, in addition to cancer, intragenic L1s may alter gene expression in a variety of diseases and abnormalities.

Show MeSH
Related in: MedlinePlus