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Epigenetic diagram showing how DNA is altered by Methylation groups. When many methyl groups (orange dots) concentrate in one area, gene expression is shut down. If the DNA has few or no methyl groups — the gene is turned on or "expressed" by cell machinery. Image Credit: Imperial College London, Department of Surgery and Cancer

Epigenome orchestrates embryo development

As the early embryo develops, cells transform into the tissues we need to make and regenerate life. Now, science is finding this process is largely controlled not by our genes, but by the epigenome, the environmental chemical markers that latch onto our DNA and initiate which genes are to be turned on or off.

Studying zebrafish embryos, researchers at Washington University School of Medicine in St. Louis have shown that the epigenome plays a significant part in guiding development in the first 24 hours after fertilization. The research, which appeared Feb. 20 in the journal Nature Communications, deepens our understanding of congenital defects and miscarriage.

The epigenome is a bit like software that interprets the DNA code hard-wired into each of our body's cells. While the DNA hardware is the same in each cell, differences in the epigenome — the software — differentiates brain cells from muscle, skin, eye or heart cells.

Using zebrafish as a model of vertebrate animals, the new study is the first to map changes in the epigenome of whole embryos and follow gene regulation during the earliest moments of development.

"Our study suggests that an underappreciated fraction of the genome is involved in gene regulation.

"Another surprising finding is that many of the important regions of DNA we identified are pretty far from the genes they regulate.

"The field has long been focused on identifying genes that manufacture proteins. We show the epigenome is just as important and is largely uncharted."

Ting Wang PhD, senior author, Principal Investigator, Roadmap Epigenomics Program, Assistant Professor, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.

Wang is a principal investigator on the Roadmap Epigenomics Program, a national initiative to map the human epigenome. Researchers leading this program recently published large data sets detailing information about human epigenetics.

Wang: "In humans, for ethical reasons, we only look at tissues in childhood and adulthood and describe differences between cell types. But with zebrafish, we can watch developmental processes unfold."

Wang and first author Hyung Joo Lee (a graduate student in Wang's lab) studied zebrafish embryos at five intervals following fertilization, stopping at the 24-hour mark when an embryo starts to develop separate tissues.

At each of these 5 points in time, investigators measured several ways the epigenome regulates gene expression, one of the most important being methyl groups. Methyl groups are organic compounds that attach to the DNA in different locations adding a carbon molecule.

When many methyl groups concentrate in one area, gene expression is shut down and that segment of DNA is packaged away. If the DNA is demethylated — with few or no methyl groups — then the genes are unpackaged by cell machinery and the gene becomes "expressed."

Most studies of DNA methylation have focused on areas close to genes called promoter regions that function like switches to turn gene expression on or off. Wang: "But our data show that only 5 percent of DNA methylation changes happen in conventionally defined promoter regions."

The scientists were surprised to discover 95 percent of methylation change occurs in regions far away from genes or their promoters — in parts of the genome considered noncoding because cell machinery is not nearby to enlist in making a particular protein.

At distant sites, losing methyl groups tended to increase gene expression. And it was seen that a graduated loss of methyl groups increased as stages of development progressed. Using various techniques, researchers correlated the loss of methyl groups in one location with the increase of gene expression in another.

Scientists surmised that noncoding regions function as developmental enhancers.

This concept allowed researchers to statistically predict which noncoding regions of the genome were potentially turning on expression of distant genes.

They verified 20 noncoding regions in zebrafish, thus explaining why 20 enhancer regions promoted developmental genes to become defined tissues, such as the eye or parts of the brain and spinal cord.

Wang: "This study suggests that many diseases may have an epigenetic origin. Even if there is nothing wrong with the protein coding genes themselves, there are lots of different regulatory changes that could mess up gene expression and lead to disease."

The investigators point out that many developmental problems, whether they result in the loss of the embryo in miscarriage or to later developmental disorders, are not connected to a particular gene.

This study supports the trend of scientists to find more and more noncoding parts of the genome are essential to gene regulation.

"I'm sure there are parts of the genome for which we may never find a function. But when we look deep, we do see very complex regulatory relationships between noncoding regions and the distant genes they regulate."

Ting Wang PhD

Abstract
DNA methylation undergoes dynamic changes during development and cell differentiation. Recent genome-wide studies discovered that tissue-specific differentially methylated regions (DMRs) often overlap tissue-specific distal cis-regulatory elements. However, developmental DNA methylation dynamics of the majority of the genomic ?CpGs outside gene promoters and CpG islands has not been extensively characterized. Here, we generate and compare comprehensive DNA methylome maps of zebrafish developing embryos. From these maps, we identify thousands of developmental stage-specific DMRs (dsDMRs) across zebrafish developmental stages. The dsDMRs contain evolutionarily conserved sequences, are associated with developmental genes and are marked with active enhancer histone posttranslational modifications. Their methylation pattern correlates much stronger than promoter methylation with expression of putative target genes. When tested in vivo using a transgenic zebrafish assay, 20 out of 20 selected candidate dsDMRs exhibit functional enhancer activities. Our data suggest that developmental enhancers are a major target of DNA methylation changes during embryogenesis.

Authors
Lee HJ, Lowdon RF, Maricque B, Zhang B, Stevens M, Li D, Johnson SL, Wang T. Developmental enhancers revealed by extensive DNA methylome maps of zebrafish early embryos. Nature Communications. Feb. 20, 2015.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

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