05 Sep 2014

Ever since scientists sequenced the first human genome in 2003, they have tried to finger regulatory influences that dictate when and where a person’s 21,000 or so genes are expressed. To help, the National Human Genome Research Institute (NHGRI) launched the Encyclopedia of DNA Elements (ENCODE) in 2003 and the Model Organism ENCODE (modENCODE) in 2007. These projects aim to identify and compare non-coding functional elements in the genomes of humans, the fruit fly Drosophila melanogaster, and the roundworm Caenorhabditis elegans. Five papers in the August 28 Nature detail the latest results from ENCODE and modENCODE, adding more than 1,600 novel transcription datasets and bringing the new total to 3,300.

Noting the importance of these contributions, Felix Muerdter and Alexander Stark of the Research Institute of Molecular Pathology in Vienna wrote in an accompanying News and Views article that “more complete genome annotations will form the basis for improved genetic studies in D. melanogaster and C. elegans—organisms that have already contributed most to our understanding of animal development and the molecular mechanisms involved.”

ENCODE and modENCODE are organized as consortia, and all data are publicly available. Participating researchers previously reported that 80 percent of the genome, much of it previously thought to comprise junk DNA, contains regulatory elements (see Sep 2012 news story). The current batch of papers looks at the regulatory elements in more detail and compares them among humans, flies, and worms.

The data will likely help researchers interpret data from animal models and better understand mutations that associate with human disorders, including neurodegenerative diseases. “Genome-wide association studies have shown that most common variations that influence disease risk are in uncharacterized regulatory elements,” John Hardy of University College London wrote to Alzforum in an email. “This increase in our understanding of gene regulation will be needed for us to develop a complete understanding of the mechanisms underpinning many of the risk loci identified.”

Two of the studies look specifically at the transcriptome. Mark Gerstein, Yale University, New Haven, Connecticut, and colleagues identified developmental gene programs the three species have in common, revealing conserved features of transcription. Focusing just on the fly, researchers including James Brown at Lawrence Berkeley National Laboratory, California, analyzed genes, RNA transcripts, and proteins expressed in various tissues during development and under environmental perturbations, such as cold shock or exposure to toxins. The researchers found that certain genes are expressed only under cellular stress, suggesting that they could be overlooked in standard laboratory experiments, wrote Muerdter and Stark.

Others examine regulatory elements in the genome. Scientists including Carlos Araya, Stanford University School of Medicine, California, mapped the binding spots for 92 transcription factors, RNA-polymerase subunits, and chromatin-associated factors over different developmental stages in the worm. Likewise, researchers including Alan Boyle, also from Stanford, presented genome-wide maps of the binding regions for a total of 310 transcription factors in humans, flies, and worms. Curiously, they report that while the structural and binding properties of these proteins are conserved from worms to humans, they target distinct genes in each organism. 

Meanwhile, the paper authored by Joshua Ho, Harvard Medical School, Boston, compared chromatin organization among the three organisms. People, flies, and worms largely share histone-modification patterns near genes and regulatory regions, but they differ in the location and composition of some features, especially in repressive chromatin near silent genes. The comparative analyses will help make experimental results from animal models more relevant to humans, and shed light on how modifications in chromatin regulate genome functions, wrote the authors. In recent years, AD researchers have turned an eye toward epigenetic research, finding differences in the epigenome between brains of AD patients and healthy controls (see Aug 2014 news story).—Gwyneth Dickey Zakaib

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References

News Citations

1. ENCODE Turns Human Genome From Sequence to Machine 19 Sep 2012
2. Alzheimer’s Brains Mottled with Epigenetic Changes 21 Aug 2014

External Citations

1. ENCODE
2. modENCODE

Further Reading

Papers

1. Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, Ward LD, Birney E, Crawford GE, Dekker J, Dunham I, Elnitski LL, Farnham PJ, Feingold EA, Gerstein M, Giddings MC, Gilbert DM, Gingeras TR, Green ED, Guigo R, Hubbard T, Kent J, Lieb JD, Myers RM, Pazin MJ, Ren B, Stamatoyannopoulos JA, Weng Z, White KP, Hardison RC. Defining functional DNA elements in the human genome. Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6131-8. Epub 2014 Apr 21 PubMed.
2. Satoh J, Kawana N, Yamamoto Y. Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases. Gene Regul Syst Bio. 2013;7:139-52. Epub 2013 Nov 4 PubMed.
3. Celniker SE, Dillon LA, Gerstein MB, Gunsalus KC, Henikoff S, Karpen GH, Kellis M, Lai EC, Lieb JD, MacAlpine DM, Micklem G, Piano F, Snyder M, Stein L, White KP, Waterston RH, modENCODE Consortium. Unlocking the secrets of the genome. Nature. 2009 Jun 18;459(7249):927-30. PubMed.
4. ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science. 2004 Oct 22;306(5696):636-40. PubMed.

News

1. ENCODE Turns Human Genome From Sequence to Machine 19 Sep 2012
2. Newly Mapped DNA Elements Help Interpret GWAS 20 Sep 2012
3. Genetics Project Update: Over 1,000 Genomes and Counting 6 Nov 2012
4. Thousands of Whole Genomes to Be Mined for New Clues to AD 26 Oct 2012
5. RNA Sequencing Helps Identify Functional Variants from GWAS 27 Sep 2013