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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 diagram shows the 4 groups of significant siRNA genes that are associated with strand of L1s: (1) siRNA genes that were associated with genes containing sense L1s or antisense L1s (+, +), (2) siRNA genes that were associated with genes containing only sense L1s (+, -), (3) siRNA genes that were associated with genes containing only antisense L1s (−, +) and (4) siRNA genes that were not associated with genes containing sense L1s or antisense L1s (−, -) but were associated with genes containing both sense and antisense L1s.
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Figure 3: The diagram shows the 4 groups of significant siRNA genes that are associated with strand of L1s: (1) siRNA genes that were associated with genes containing sense L1s or antisense L1s (+, +), (2) siRNA genes that were associated with genes containing only sense L1s (+, -), (3) siRNA genes that were associated with genes containing only antisense L1s (−, +) and (4) siRNA genes that were not associated with genes containing sense L1s or antisense L1s (−, -) but were associated with genes containing both sense and antisense L1s.

Mentions: Host genes of sense and antisense L1s were used to build the libraries and were analyzed by Pearson’s chi-square test and a permutation test using all of the experiments and all of the intragenic L1s. The results revealed that 15 and 12 experiments promoted the downregulation (OR > 1) and upregulation (OR > 1), respectively, of genes containing sense L1s. In contrast, 4 significant groups contained genes with antisense L1s: 39 experiments were associated with an OR greater than 1 with downregulation, 4 experiments were associated with an OR less than 1 with upregulation, 28 experiments were associated with an OR greater than 1 with upregulation, and 3 experiments were associated with an OR greater than 1 with downregulation and upregulation. Using strand-dependent intragenic L1s, the significant siRNA genes were categorized into 4 groups. The first group contained 13 siRNA genes that were associated with genes containing sense L1s and genes containing antisense L1s. There were 12 siRNA genes associated with genes containing sense L1s, whereas 41 siRNA genes were associated with genes containing antisense L1s. The last group, which consisted of 19 siRNA genes, exhibited significant association only when all genes containing L1s were used in the analysis (Figure 3 and Additional file 1: Table S1).


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 diagram shows the 4 groups of significant siRNA genes that are associated with strand of L1s: (1) siRNA genes that were associated with genes containing sense L1s or antisense L1s (+, +), (2) siRNA genes that were associated with genes containing only sense L1s (+, -), (3) siRNA genes that were associated with genes containing only antisense L1s (−, +) and (4) siRNA genes that were not associated with genes containing sense L1s or antisense L1s (−, -) but were associated with genes containing both sense and antisense L1s.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: The diagram shows the 4 groups of significant siRNA genes that are associated with strand of L1s: (1) siRNA genes that were associated with genes containing sense L1s or antisense L1s (+, +), (2) siRNA genes that were associated with genes containing only sense L1s (+, -), (3) siRNA genes that were associated with genes containing only antisense L1s (−, +) and (4) siRNA genes that were not associated with genes containing sense L1s or antisense L1s (−, -) but were associated with genes containing both sense and antisense L1s.
Mentions: Host genes of sense and antisense L1s were used to build the libraries and were analyzed by Pearson’s chi-square test and a permutation test using all of the experiments and all of the intragenic L1s. The results revealed that 15 and 12 experiments promoted the downregulation (OR > 1) and upregulation (OR > 1), respectively, of genes containing sense L1s. In contrast, 4 significant groups contained genes with antisense L1s: 39 experiments were associated with an OR greater than 1 with downregulation, 4 experiments were associated with an OR less than 1 with upregulation, 28 experiments were associated with an OR greater than 1 with upregulation, and 3 experiments were associated with an OR greater than 1 with downregulation and upregulation. Using strand-dependent intragenic L1s, the significant siRNA genes were categorized into 4 groups. The first group contained 13 siRNA genes that were associated with genes containing sense L1s and genes containing antisense L1s. There were 12 siRNA genes associated with genes containing sense L1s, whereas 41 siRNA genes were associated with genes containing antisense L1s. The last group, which consisted of 19 siRNA genes, exhibited significant association only when all genes containing L1s were used in the analysis (Figure 3 and Additional file 1: Table S1).

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