Callipyge mutation affects gene expression in cis: a potential role for chromatin structure

Area of Science:

• Genetics
• Epigenetics
• Animal Science

Background:

• The callipyge sheep mutation causes muscle hypertrophy due to a genetic alteration between the DLK1 and MEG3 genes.
• The exact mechanism linking this mutation to muscle growth, particularly involving DLK1 overexpression, remains unclear.

Purpose of the Study:

• To investigate the role of CLPG1 transcripts in callipyge sheep muscle hypertrophy.
• To elucidate the epigenetic mechanisms, specifically DNA methylation, influenced by the callipyge mutation.

Main Methods:

• Analyzing CLPG1 transcript expression across different genotypes and developmental stages.
• Assessing CpG methylation patterns in the longissimus dorsi muscle of normal and callipyge sheep.
• Correlating epigenetic changes with gene expression and phenotypic manifestation.

Main Results:

• Postnatal CLPG1 expression is restricted to mutated alleles in callipyge sheep, unlike biallelic prenatal expression.
• The mutation significantly represses normal postnatal CpG hypermethylation, correlating with sustained DLK1 expression and hypertrophy.
• Normal sheep exhibit postnatal hypermethylation, silencing CLPG1 and DLK1 transcription.

Conclusions:

• The callipyge mutation disrupts normal epigenetic regulation, leading to sustained prenatal gene expression patterns postnatally.
• This epigenetic dysregulation, specifically altered methylation, drives DLK1 overexpression and muscle hypertrophy in callipyge sheep.
• A proposed model explains the mutation's effects, including the normal phenotype in homozygous mutants.