September 15, 2014

Expanding Our Understanding of Genomics

At a Glance

  • By analyzing the genomes of humans, flies, and worms, scientists uncovered many common, key features.
  • The findings offer insights into embryonic development, gene regulation, and other biological processes that are vital to human biology and disease.
Illustration of fruit flies, people, and roundworms. Darryl Leja, NHGRI

The human genome sequence, published in 2003, has helped researchers identify countless genes involved in health and disease. But genes tell only part of a biological story. Many other types of DNA sequences also have biological function. These regions control gene activity and affect DNA structure, dynamics, and replication. Chromatin, the complex of DNA and protein that forms chromosomes, also affects how genes are expressed (turned on and off). In 2003, NIH’s National Human Genome Research Institute (NHGRI) launched the ENCyclopedia Of DNA Elements (ENCODE) consortium to catalog these functional elements in the human genome.

To understand the complex molecular mechanisms of genome function, researchers often turn to model organisms. In 2007, NHGRI launched modENCODE to catalog functional elements in the Caenorhabditis elegans (roundworm) and Drosophila melanogaster (fruit fly) genomes. Initial catalogs were published in 2010. Five new modENCODE papers appeared in Nature on August 28, 2014. The studies are among hundreds of modENCODE papers that have been or will be published this year to mark completion of the project.

In one study, scientists analyzed the human, fly, and worm transcriptomes—the complete collection of gene transcripts (or “readouts”). By studying more than 67 billion sequence readouts, the researchers discovered gene expression patterns shared by all 3 species. The team also found chromatin features at gene promoters—regions where cells begin transcribing DNA into RNA—that can predict expression levels in all 3 organisms.

Another group investigated how chromatin is organized and how it influences gene regulation. The scientists compared patterns of modifications in chromatin that are needed for the cell to access the DNA inside, and the changes in DNA replication patterns as a result of these modifications. They discovered that the general principles of chromatin organization are similar in all 3 species. However, the locations of these structural features in the genome vary depending on a cell’s type and state.

Another team analyzed transcription regulatory factors—key proteins that bind to DNA and regulate genes to control a cell’s development and activity. The researchers mapped the binding locations of these factors in all 3 species in diverse cell types, developmental stages, and conditions. They found that the general principles of gene regulation are conserved between species. Transcription factors tend to bind to similar DNA sequences and coordinate similar regulatory networks. However, the regulatory targets and binding patterns differ significantly across species. Transcription factors are also mostly expressed at different times depending on the developmental stage and other conditions.

“One way to describe and understand the human genome is through comparative genomics and studying model organisms,” explains Dr. Mark Gerstein of Yale University, lead author on one of the papers.

In addition to the papers published by modENCODE researchers, hundreds of papers using ENCODE data have also been published by groups outside of the program. Together, these add a wealth of new information for use by the research community.

Related Links

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Funding: NIH’s National Human Genome Research Institute (NHGRI), National Institute of General Medical Sciences (NIGMS), and National Institute of Biomedical Imaging and Bioengineering (NIBIB); Department of Energy; Lilly Endowment; Wellcome Trust; Spanish Ministry of Education; National Natural Science Foundation of China; Ministry of Education, Science & Technology of South Korea; National Research Foundation of Korea.