How chemical changes in DNA keep genes quiet

Many diseases, including some types of cancer and some neurodevelopmental conditions, have abnormal patterns of DNA methylation, a chemical modification that regulates gene expression to keep genes in the “off” position.

Researchers at the Friedrich Miescher Institute found that DNA methylation keeps genes quiet, mostly by preventing DNA from binding with transcription factors (proteins that control how genes are expressed). The findings advance our understanding of how chemical modifications to DNA regulate gene expression.

DNA methylation is a process in which a chemical tag known as a methyl group is attached to a nucleotide, one of the building blocks of DNA. When DNA methylation occurs in “CpG islands”, regions of DNA that tend to be located near regions where gene expression is initiated, the expression of genes is turned off.

However, it is unclear what process DNA methylation mostly relies on to keep genes out: does it keep transcription factors away from the DNA molecule? Or does it indirectly silence genes by recruiting proteins called Methyl-CpG Binding Domain (MBD) proteins?

To address this question, researchers in the Schübeler lab designed the cells to be devoid of any MBD protein. They found that this did not reactivate genes suppressed by DNA methylation. However, completely eliminating DNA methylation resulted in the activation of these genes. In neurons, the researchers identified several transcription factors that do not bind to their preferred DNA binding sites when methylation is present.

The researchers say the findings show that DNA methylation mostly prevents transcription factors from binding to DNA, keeping genes quiet.

The research was published in the journal Nature Genetics.