Genomic imprinting at a boundary element flanking the SDHD locus

Area of Science:

• Genetics
• Epigenetics
• Oncology

Background:

• Germline mutations in the SDHD gene are linked to paraganglioma (PGL) predisposition.
• Tumor development is highly penetrant with paternal transmission but rarely occurs with maternal transmission.
• The mechanism behind this parent-of-origin tumor predisposition is not well understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the imprinted penetrance of SDHD mutations.
• To identify epigenetic factors that regulate SDHD expression differently based on parental origin.

Main Methods:

• Analysis of imprinted methylation at an alternative promoter of a non-coding RNA near SDHD.
• Tissue-specific methylation analysis in adrenal glands and fetal tissues.
• Assessment of CTCF and cohesin binding to investigate chromatin architecture.

Main Results:

• Identified tissue-specific imprinted methylation at a boundary element flanking SDHD.
• Observed maternal allelic hypermethylation in adrenal tissues and PGL tumors.
• Found altered chromatin looping factor binding (cohesin) correlated with methylation status.

Conclusions:

• Differential allelic methylation at a boundary element contributes to imprinted penetrance of SDHD mutations.
• Epigenetic suppression of the maternal SDHD allele is the likely mechanism for reduced tumor risk.
• This imprinting mechanism provides insight into parent-specific tumor predisposition syndromes.