The same epigenetic marks can be read as “keep off” or “welcome,” depending on what DNA-binding protein, or transcription factor, is doing the reading. These marks, methylated cytosine and guanine dinucleotides (mCpGs), normally indicate which portions of the genome are inactive. But new findings from a systematic study of hundreds of transcription factors suggest that mCpGs may play a more subtle role in gene regulation.
In this new study, scientists based at Karolinska Institutet systematically analyzed the binding specificities of transcription factors to DNA that was marked by mCpGs, as well as to DNA that was unmarked by mCpGs. The observed that mCpGs can influence binding of most transcription factors to DNA—in some cases negatively and in others positively.
Interestingly, many of the transcription factors that prefer to bind to mCpG sites appear to be important to development. This finding may inform future analyses of the role of DNA methylation on cell differentiation, chromatin reprogramming, and transcriptional regulation.
Additional details from the study appeared May 5 in Science, in a paper entitled “Impact of Cytosine Methylation on DNA Binding Specificities of Human Transcription Factors.”
“By analysis of 542 human TFs [transcription factors] with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences,” wrote the article’s authors. “Most of these are in the extended homeodomain family. Structural analysis showed that homeodomain specificity for methylcytosine depends on direct hydrophobic interactions with the methylcytosine 5-methyl group.”
“The results suggest that such 'master' regulatory factors could activate regions of the genome that are normally inactive, leading to the formation of organs during development, or the initiation of pathological changes in cells that lead to diseases such as cancer,” said Jussi Taipale, Ph.D., a professor of medical biochemistry and biophysics at the Karolinska Institutet and leader of the current study.
The results pave the way for cracking the genetic code that controls the expression of genes, and will have broad implications for the understanding of development and disease. The availability of genomic information relevant to disease is expanding at an exponentially increasing rate.
“This study identifies how the modification of the DNA structure affects the binding of transcription factors, and this increases our understanding of how genes are regulated in cells and further aids us in deciphering the grammar written into DNA,” noted Professor Taipale.