"Loss of IGF2 imprinting is associated with abrogation of long-range intrachromosomal interactions in human cancer cells".
Thanh H. Vu, An H. Nguyen and Andrew R. Hoffman*
VA Palo Alto Health Care System and Stanford University, Palo Alto, CA 94301, USA
* To whom correspondence should be addressed at: Medical Service
(111), VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA
94304, USA. Tel: +1 650 858 3930,
Email: arhoffman@stanford.edu
Received October 29, 2009; Accepted December 14, 2009
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.
1. Each cell retains all of its embryonic genes for a lifetime.
2. Controls for embryonic genes are often absent in adults.
3. Uncontrolled embryonic genes can replicate wildly.
4. Replicating genes participate in intra-cellular competition.
5. The basis for gene competition is selective transcription.
6. MicroRNAs can reprogram embryomic transcription.
7. Gene reprogramming can produce normal phenotypes.
8. Normal phenotypes can by-pass chromosomal lesions.
9. MicroRNA therapy may need to be permanent.
10. Transplantation of microRNAs could be preferred.
1. Pathways within cell genomes involve a flow of information.
2. Information can flow by direct contact or by third parties.
3. Direct contact within whole genomes is difficult to regulate.
4. DNA-DNA direct contects are influenced by agents.
5. Nuclear agents include hydrophilic ionic and hydrophobic conforming ligands.
6. Third parties within genomes involve RNAs and proteins.
7. RNAs and proteins are easy to regulate or reverse.
8. Information can be shared, lost, or transformed.
9. System information can be hidden during system isolation.
10. Local information can be permanently lost during system entropy.
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