Large-scale methylation domains mark a functional subset of neuronally expressed genes

Area of Science:

• Epigenetics
• Genomics
• Neuroscience

Background:

• DNA methylation is crucial for cell differentiation, but its function in most genomic regions remains unclear.
• Human cells exhibit highly methylated domains (HMDs) and partially methylated domains (PMDs).
• PMDs were previously identified in IMR90 cells and their presence in neuronal cells was investigated.

Purpose of the Study:

• To investigate the presence and genomic distribution of partially methylated domains (PMDs) in human neuronal cells.
• To develop computational methods for mapping PMDs and analyze their relationship with gene expression and disease.
• To explore the potential role of PMDs in the etiology of autism.

Main Methods:

• Bisulfite conversion and high-throughput sequencing (MethylC-seq) were employed to profile DNA methylation.
• A novel hidden Markov model (HMM) was developed to computationally identify and map PMDs.
• Genomic regions, gene expression, and associated functions were analyzed in relation to PMD status.

Main Results:

• Partially methylated domains (PMDs) were discovered in human SH-SY5Y neuronal cells, similar to IMR90 cells.
• PMDs can span large genomic regions (up to 9 Mb) and cover significant portions of the genome (19-41%).
• PMDs are associated with repressed transcription and tissue-specific gene expression; neuronal HMDs are enriched for neuronal functions, and PMDs harbor autism candidate genes.

Conclusions:

• Large-scale DNA methylation domains, including PMDs, are a feature of the human genome with implications for cell differentiation and gene regulation.
• PMDs are linked to tissue-specific gene expression and may play a role in neuronal function.
• The enrichment of autism candidate genes within PMDs suggests their relevance to understanding autism etiology.