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Loss of IGF2 imprinting is associated with abrogation of long-range intrachromosomal interactions in human cancer cells.

ABSTRACT: Nuclear architecture and chromatin geography are important factors in the regulation of gene expression, as these components may play a vital epigenetic role both in normal physiology as well as in the initiation and progression of malignancies. Using a modification of the chromosome conformation capture (3C) technique, we examined long-range chromatin interactions of the imprinted human IGF2 gene. We demonstrate that numerous intrachromosomal interactions occur along both parental alleles in normal tissues, where the IGF2 is paternally expressed, as well as in normal liver where gene expression is biallelic. Long-range and allele-specific interactions occur between the IGF2/H19 imprinting control region-1 (ICR1) and ICR2, a region which regulates an imprinted gene cluster nearly a megabase distant from IGF2. Loss of genomic imprinting is a common epigenetic event in cancer, and long-range interactions have not been examined in malignant cells. In cancer cell lines in which IGF2 imprinting is maintained (MOI), essentially all of the 3C interactions seen in normal cells were preserved. However, in cells in which IGF2 imprinting was lost (LOI), nearly all of the long-range chromatin interactions involving IGF2 were abrogated. A three-dimensional computer model depicts the physical interactions between the IGF2 promoter and ICR1 in MOI cells, while the model of LOI lung cancer cells is flattened with few long-range interactions. This dramatic change in the three-dimension configuration of the chromatin at the IGF2 locus in LOI cancer cells suggests that the loss of imprinting may lead to a variety of changes in gene expression in addition to changes in IGF2 transcription.

SUBMITTER: Vu TH

PROVIDER: S-EPMC2816615 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Loss of IGF2 imprinting is associated with abrogation of long-range intrachromosomal interactions in human cancer cells.

Vu Thanh H TH Nguyen An H AH Hoffman Andrew R AR

Human molecular genetics 20091216 5

Nuclear architecture and chromatin geography are important factors in the regulation of gene expression, as these components may play a vital epigenetic role both in normal physiology as well as in the initiation and progression of malignancies. Using a modification of the chromosome conformation capture (3C) technique, we examined long-range chromatin interactions of the imprinted human IGF2 gene. We demonstrate that numerous intrachromosomal interactions occur along both parental alleles in no ...[more]

PMID: 20015958

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Project description:Loss of imprinting (LOI) of the IGF2 gene (which encodes insulin-like growth factor II) is the most common genetic or epigenetic alteration in Wilms tumor; LOI involves aberrant activation of the normally repressed maternally inherited allele. We found previously that LOI of IGF2 occurs in approximately half of all Wilms tumors (i.e., those arising from lineage-committed nephrogenic progenitor cells). We investigated whether LOI of IGF2 is associated with relaxation of imprinting at loci other than IGF2 or with widespread alterations in DNA methylation. We stratified 59 Wilms tumor samples by IGF2 LOI status by use of hot-stop reverse transcription-polymerase chain reaction and/or methylation analysis of the differentially methylated region of the H19 gene and identified 31 samples with and 28 without LOI. We used quantitative allele-specific expression analysis to determine whether six other imprinted genes (i.e., H19, KCNQ1, LIT1, TSSC5, GRB10, and MEG3) had subtle LOI. No statistically significant difference in allele-specific expression between Wilms tumor with or without LOI was found for LIT1, TSSC5, GRB10, and MEG3. For the KCNQ1 gene there was a slight difference between the groups with (37.0%, 95% confidence interval [CI] = 31.8% to 42.2%) and without (27.7%, 95% CI = 21.8% to 33.5%) LOI (P = .02 for F test of group differences in a mixed-effects model). For H19, we also found a slight difference between the groups with (7.5%, 95% CI = 2.4% to 12.7%) and without (2.2%, 95% CI = -3.2% to 7.6%) LOI of IGF2 (P = .15 for F test). In 27 tumor samples, we also used a microarray technique to analyze methylation of 378 genes, 38 of which were suspected or confirmed imprinted genes. We found that statistically significant alterations in only the differentially methylated region of the H19 gene were associated with LOI of IGF2. Thus, epigenetic alterations in Wilms tumors are not widespread, supporting the gene and lineage specificity of LOI of IGF2.

Dataset Information

Loss of IGF2 imprinting is associated with abrogation of long-range intrachromosomal interactions in human cancer cells.

Publications

Loss of IGF2 imprinting is associated with abrogation of long-range intrachromosomal interactions in human cancer cells.

Similar Datasets

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