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Multiple cis elements within the Igf2/H19 insulator domain organize a distance-dependent silencer. A cautionary note
Vasudeva Ginjala1, Claes Holmgren, Erik Ullerås
1Department of Development & Genetics, Evolution Biology Centre, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden.
The Journal of Biological Chemistry
|January 5, 2002
Summary
The H19 imprinting control region (ICR) acts as a silencer near promoters, independent of histone deacetylase functions. Its distance from the promoter is crucial for interpreting insulator and silencer data accurately.
Area of Science:
- Genetics
- Epigenetics
- Molecular Biology
Background:
- The H19 gene's 5'-flank contains a differentially methylated imprinting control region (ICR).
- This ICR normally represses maternal Igf2 and paternal H19 alleles.
Purpose of the Study:
- To investigate the H19 ICR's function as a silencer.
- To determine the role of promoter proximity and histone deacetylase activity in H19 ICR-mediated silencing.
- To evaluate the impact of distance on the interpretation of insulator/silencer data.
Main Methods:
- Deletion analyses to map the silencing feature within the ICR.
- Trichostatin A treatment to assess the involvement of histone deacetylase functions.
- Chromatin immunopurification to analyze histone acetylation at the promoter region.
Main Results:
- The H19 ICR functions as a potent silencer in a promoter-proximal position.
- Silencing is not affected by trichostatin A, suggesting no histone deacetylase involvement.
- H19 ICR-mediated silencing is distance-dependent; activity increases when separated from the promoter by over 1.2 kb.
- The ICR prevents histone reacetylation in a proximal but not distal position.
Conclusions:
- The H19 ICR's potent silencing in proximity to promoters may be a side effect, not the primary mechanism for paternal H19 allele silencing.
- Distance is a critical factor in interpreting the function of insulator and silencer elements.