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The histone code regulating expression of the imprinted mouse Igf2r gene.
Youwen Yang1, Tao Li, Thanh H Vu
1Medical Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304. arhoffman@stanford.edu
Endocrinology
|September 17, 2003
Summary
Mouse Igf2r and Air imprinting involves specific histone modifications at differentially methylated regions. Tissue-specific Igf2r expression, particularly in the brain, correlates with altered histone marks, suggesting a flexible imprinting mechanism.
Area of Science:
- Genetics
- Epigenetics
- Genomic Imprinting
Background:
- The mouse Insulin-like Growth Factor 2 Receptor (Igf2r) and its antisense transcript Air are reciprocally imprinted in most tissues.
- Mechanisms like Air-mediated silencing and differentially methylated regions (DMRs) have been proposed to explain this imprinting.
- Understanding these mechanisms is crucial for comprehending gene regulation and developmental processes.
Purpose of the Study:
- To investigate allele-specific histone modifications in the DMRs of mouse Igf2r and Air.
- To elucidate the role of histone modifications in establishing and maintaining Igf2r-Air imprinting.
- To explore the basis for tissue-specific relaxation of Igf2r imprinting.
Main Methods:
- Utilized Mus musculus x Mus spretus interspecific mice.
- Employed chromatin immunoprecipitation (ChIP) to analyze allele-specific histone modifications (acetylation, H3 K9-Ac, H3 K4-Me, H3 K9 methylation, H3 S10 phosphorylation) at DMR1 and DMR2.
- Used chemical treatments (5-aza-deoxycytidine, Trichostatin A) on fibroblast cells to assess the impact on gene expression and histone modifications.
Main Results:
- Active alleles of Igf2r and Air showed association with acetylated histones (H3, H4), H3 K9-Ac, and H3 K4-Me.
- Silenced alleles were linked to DNA methylation, deacetylated H3 K9, and unmethylated H3 K4.
- DMR2 exhibited allele-specific histone modifications, including H3 K9 methylation on silenced alleles and H3 S10 phosphorylation on active alleles in specific tissues.
- Reactivation of the silenced allele in fibroblast cells correlated with biallelic histone acetylation.
- Tissue-specific relaxation of Igf2r imprinting in the central nervous system was associated with biallelic histone acetylation and H3 K4 methylation at DMR1.
Conclusions:
- Proposed a model for the histone code governing Igf2r and Air imprinting, differentiating marks at the gametic imprint DMR2.
- Explained tissue-specific imprinting of Igf2r in mice and the absence of IGF2R imprinting in humans based on histone modification patterns.
- Highlighted the dynamic nature of epigenetic regulation in controlling imprinted gene expression.