De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency

Area of Science:

• Epigenetics
• Developmental Biology
• Cancer Biology

Background:

• CpG islands (CGIs) are typically protected from de novo methylation in somatic cells.
• Cancer cells frequently display CGI hypermethylation, suggesting epigenetic regulatory defects.
• Imprinting control regions (ICRs) are crucial for genomic imprinting and are normally protected from methylation.

Purpose of the Study:

• To investigate CGI methylation dynamics during somatic cell reprogramming.
• To identify specific regions prone to de novo methylation in reprogrammed cells.
• To explore the link between CGI methylation patterns and cancer pathogenesis, particularly pediatric cancers.

Main Methods:

• Comprehensive analysis of CGI methylation during somatic cell reprogramming.
• Comparison of methylation patterns in reprogrammed cells with human pluripotent stem cells (PSCs) and various cancer types.
• Functional studies involving the ablation of DNA methyltransferase 3A (Dnmt3a) in PSCs.

Main Results:

• Most CGIs remained hypomethylated during reprogramming, but a subset, particularly at ICRs, underwent de novo methylation in reprogrammed PSCs.
• De novo ICR methylation correlated with the late-stage silencing of reprogramming factors.
• ICR-preferred CGI hypermethylation was observed in human PSCs and pediatric cancers, contrasting with the genome-wide CGI hypermethylation in adult cancers.
• Dnmt3a ablation prevented de novo ICR methylation in PSCs.

Conclusions:

• Somatic cell reprogramming can lead to aberrant de novo methylation at specific CGIs, notably ICRs.
• This ICR-specific CGI hypermethylation in PSCs mirrors patterns observed in pediatric cancers, suggesting a potential role in disease development.
• Dnmt3a is critical for mediating de novo ICR methylation during reprogramming.
• Understanding these epigenetic alterations has implications for both PSC applications and pediatric cancer pathogenesis.