Researchers map DNA methylation changes to study developmental disorders

In an effort to enlighten the causes of human developmental disorders, researchers from Salk Institute performed a study in which they created a total of 168 new maps of chemical marks on DNA strands, known as methylation, in developing mice.

The information was recently published in a special edition of the Nature journal, dedicated to the ENCODE Project, on July 29^th, 2020. The ENCODE Project is a public research effort that is aiming to identify all functional elements in the mouse and human genomes.

The latest data can help narrow down areas of the human genome that are implicated in various diseases, like Rett syndrome and schizophrenia. The study’s authors are also on two more papers in the special edition.

This is the only available data set that looks at the methylation in a developing mouse over time, tissue by tissue. It’s going to be a valuable resource to help in narrowing down the causal tissues of human developmental diseases.”

Joseph Ecker, Study Senior Author and Professor, Genomic Analysis Laboratory, Salk Institute

Ecker is also a Howard Hughes Medical Institute Investigator.

While the DNA sequence found in each cell of the human body is almost identical, chemical marks present on those DNA strands provide unique identities to the cells. For example, the methylation patterns on adult brain cells are different from those found on adult liver cells.

That is partly attributed to short stretches in the genome known as enhancers. When transcription factor proteins attach to the regions of this enhancer, a target gene would be probably expressed.

But when an enhancer is methylated, transcription factors usually do not adhere together and the related gene is less likely to be stimulated; such methyl marks are similar to applying the hand brake after parking a vehicle.

Scientists already know that mutations that occur in these enhancer areas—by impacting the expression levels of an equivalent gene—can lead to diseases. However, there are countless numbers of enhancers and these can be situated far away from the gene controlled by them.

Hence, narrowing down the type of enhancer modifications that may contribute to a developmental disease has been a difficult task.

In the latest study, Ecker and his colleagues used computational algorithms and experimental methods that they earlier defined to analyze the DNA methylation patterns of cells present in samples of a dozen tissue types isolated from mice across eight developmental phases.

The breadth of samples that we applied this technology to is what’s really key.”

Yupeng He, Study First Author and Postdoctoral Research Fellow, Salk Institute

Yupeng He is presently a senior bioinformatics scientist at Guardant Health.

The researchers identified over 1.8 million areas of the mouse genome that had differences in methylation based on developmental stage, tissue, or both. During the early development stage, such alterations were mostly the loss of methylation on DNA—similar to removing the brake on the expression of genes and allowing the developmental genes to switch on.

But after birth, a majority of the sites once again became highly methylated, applying the brakes on the expression of genes as the mouse nears birth.

We think that the removal of methylation makes the whole genome more open to dynamic regulation during development. After birth, genes critical for early development need to be more stably silenced because we don’t want them turned on in mature tissue, so that’s when methylation comes in and helps shut down the early developmental enhancers.”

Yupeng He, Study First Author and Postdoctoral Research Fellow, Salk Institute

Earlier, several scientists had analyzed methylation by focusing on genomic regions close to genes known as CpG islands—DNA sections that contain plenty of guanine and cytosine base pairs, since normal methylation takes place upon the addition of methyl to a cytosine followed by a guanine. But in the latest study, Yupeng He and Ecker demonstrated that 91.5% of the methylation changes found by them during development are far away from CpG islands.

Yupeng He added, “If you only look at those CpG island regions near genes, as many people do, you’ll miss a lot of the meaningful DNA changes that could be directly related to your research questions.”

To demonstrate the utility of their novel data set, the scientists studied genetic changes that had been associated with 27 human disorders and diseases in earlier genome-wide association studies (GWAS). They identified the links between certain human disease mutations and tissue-specific patterns of methylation in matching sites of the mouse genome.

For example, schizophrenia-associated mutations were more likely to be detected in suspected gene control areas in the mouse genome that go through methylation changes in the brain region, known as the forebrain, at the time of development. Patterns like these could help other scientists to narrow down the type of mutations found in a GWAS that should be focused by them.

Salk team maps functional areas of the mouse genome over time to better understand disease. Video Credit: He et al., Nature.