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An upstream insulator regulates DLK1 imprinting in AML
Haytham Khoury1, Fernando Suarez-Saiz, Samantha Wu
1Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada.
Blood
|January 22, 2010
Summary
Biallelic expression of the DLK1 gene in acute myeloid leukemia (AML) is linked to hypermethylation upstream of DLK1. This suggests an insulator region regulates DLK1 imprinting in AML.
Area of Science:
- Genetics and Epigenetics
- Cancer Biology
Background:
- The imprinted gene DLK1, located on chromosome 14, exhibits monoallelic expression in normal bone marrow.
- Aberrant DLK1 expression is observed in a significant portion of acute myeloid leukemia (AML) cases.
Purpose of the Study:
- To investigate the mechanism regulating DLK1 expression in AML.
- To determine the role of methylation and regulatory elements in DLK1 imprinting during AML development.
Main Methods:
- Analysis of DLK1 expression using informative coding single nucleotide polymorphisms.
- Quantitative methylation analysis of CpG-rich regions near DLK1 and MEG3.
- Allele-specific methylation analysis and chromatin immunoprecipitation assays.
Main Results:
- Biallelic DLK1 expression was detected in 76% of DLK1-overexpressing AML cases (61% of all AML).
- Hypermethylation of a CpG-rich region 18 kb upstream of DLK1 strongly associated with biallelic DLK1 expression.
- Differential methylation of this upstream region in normal bone marrow and monoallelic AML, contrasted with biallelic methylation in AML with biallelic expression; CCTC-binding factor binding was lost in biallelic expression samples.
Conclusions:
- An insulator element located 18 kb upstream of DLK1 is crucial for regulating its imprinting.
- Aberrant methylation and loss of insulator function contribute to biallelic DLK1 expression in AML.
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