How to place a chemical tag to control a gene
Biochemists have developed a program that predicts where to place chemical tags to control gene activity.
The epigenome guides the development of all complex organisms from their beginnings as single fertilized eggs. Researchers analyzed epigenomic patterns in human embryonic stem cells (ESCs) and four cell lines derived from ESCs in order to create a catalogue of genetic elements that shape the epigenome as an embryo developes into an adult.
Damage to the epigenome not only disrupts infant development, but can happen at any point in our lives and lead to illness.
By editing DNA sequences that control epigenome modifications, scientists begin to understand how each guide functions and perhaps, in the future, may be able to mend epigenomic mistakes that cause harm.
By comparing sequences with and without epigenome modifications, the researchers identified DNA patterns associated with change. They called their program Epigram and have made both the program and the DNA motifs they have identified openly available to other scientists.
Their results are published in Nature Methods.
"All of our cells have the same blueprint – the same DNA – although they serve separate functions. Skin cells protect us, nerve cells send signals, and differences emerge when different subsets of genes are active or silent within particular groups of cells."
John Whitaker, lead author on the report.
These patterns of activity are controlled by modifying DNA, but not altering its sequence—chemical tags can influence which genes are read and which are skipped within a particular cell.
"The interplay between genetic and epigenomic regulation has only begun to be deciphered. This study revealed that there are specific DNA sequences that are recognized by DNA-binding proteins, which specify exactly where other enzymes place epigenomic marks."
Wei Wang, professor of chemistry and biochemistry who directed the work.
The epigenome is established and maintained by the site-specific recruitment of chromatin-modifying enzymes and their cofactors. Identifying the cis elements that regulate epigenomic modification is critical for understanding the regulatory mechanisms that control gene expression patterns. We present Epigram, an analysis pipeline that predicts histone modification and DNA methylation patterns from DNA motifs. The identified cis elements represent interactions with the site-specific DNA-binding factors that establish and maintain epigenomic modifications. We cataloged the cis elements in embryonic stem cells and four derived lineages and found numerous motifs that have location preference, such as at the center of H3K27ac or at the edges of H3K4me3 and H3K9me3, which provides mechanistic insight about the shaping of the epigenome. The Epigram pipeline and predictive motifs are at http://wanglab.ucsd.edu/star/epigram/.
Additional author Zhao Chen is a postdoctoral researcher working with Wang. John Whitaker, a former postdoctoral researcher in the group now works for Janssen Pharmaceutical Companies of Johnson & Johnson. A grant from the National Institute of Environmental Health Sciences to the San Diego Epigenome Center partially supported this work.
Return to top of page