Genomic Researchers Map Embryonic DNA and Histone Methylation Patterns

Cells manage gene expression by wrapping DNA around clusters of globular histone proteins to form nucleosomes. These nucleosomes of DNA and histones are organized into chromatin. Changes to the structure of chromatin influence gene expression: genes are inactivated when the chromatin is condensed, and they are expressed when chromatin is open. These dynamic chromatin states are controlled by reversible epigenetic patterns of DNA methylation and histone modifications. Enzymes involved in this process include DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone acetylases, histone methyltransferases and the methyl-binding domain protein MECP2. Alterations in these normal epigenetic patterns can deregulate patterns of gene expression, which results in profound and diverse clinical outcomes.

In addition to DNA methylation, changes to histone proteins orchestrate DNA organization and gene expression. Histone-modifying enzymes are recruited to ensure that a receptive DNA region is either accessible for transcription or that DNA is targeted for silencing. Active regions of chromatin have unmethylated DNA and have high levels of acetylated histones, whereas inactive regions of chromatin contain methylated DNA and deacetylated histones.

As participants in the [US] National Institutes of Health's (Bethesda, MD, USA) Epigenome Roadmap Project investigators at the University of California, San Diego (USA; UCSD) and the Morgridge Institute for Research (Madison, WI, USA) delved into the processes that control the epigenetic regulation of embryonic development. To do this they differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage.

They reported in the May 9, 2013, online edition of the journal Cell that DNA promoter regions that were active in early developmental stages tended to be CG (cytosine/guanine) rich and mainly silenced by histone tri-methylation. By contrast, promoters for genes expressed preferentially at later stages were often CG poor and primarily employed DNA methylation upon repression. The early developmental regulatory genes were often located in large genomic domains that were generally devoid of DNA methylation in most lineages, which the investigators termed DNA methylation valleys (DMVs).

“By applying large-scale genomics technologies, we could explore how genes across the genome are turned on and off as embryonic cells and their descendant lineages choose their fates, determining which parts of the body they would generate,” said senior author Dr. Bing Ren, assistant professor of cellular and molecular medicine at UCSD. “These data are going to be very useful to the scientific community in understanding the logic of early human development. But I think our main contribution is the creation of a major information resource for biomedical research. Many complex diseases have their roots in early human development.”

Related Links:
[US] National Institutes of Health
University of California, San Diego
Morgridge Institute for Research