Trans allele methylation and paramutation-like effects in mice

Area of Science:

• Genetics
• Epigenetics
• Genomic imprinting

Background:

• Mammalian imprinted genes exhibit parent-of-origin-specific DNA methylation and allele-specific expression.
• The Rasgrf1 gene requires a repeated DNA element for paternal allele methylation and expression.
• The Igf2r gene's maternal allele methylation depends on a sequence known as region 2.

Purpose of the Study:

• To investigate if methylation control sequences can function ectopically.
• To determine if altering Rasgrf1's regulatory elements affects its methylation and expression.
• To explore the potential for trans-allelic interactions and epigenetic memory in imprinted genes.

Main Methods:

• Gene editing in mice to replace the Rasgrf1 repeats on the paternal allele with the Igf2r region 2 sequence.
• Analysis of DNA methylation patterns and gene expression levels in offspring.
• Assessment of epigenetic inheritance across generations.

Main Results:

• Replacing Rasgrf1 repeats with region 2 enabled methylation and expression of the paternal Rasgrf1 allele.
• Paternal transmission of the modified allele induced methylation and expression of the silent maternal Rasgrf1 allele (in trans).
• The activated maternal allele maintained its state in the subsequent generation, independent of the paternal allele.

Conclusions:

• Methylation control sequences can function ectopically, demonstrating sequence-independent regulatory potential.
• The study demonstrates a phenomenon in mice analogous to paramutation observed in plants, involving trans-allelic epigenetic regulation.
• Rasgrf1 epigenetic states can be established and stably inherited, suggesting a mechanism for epigenetic memory.