The National Human Genome Research Institute announced in September the results of a five-year international study of the regulation and organization of the human genome. The project is named ENCODE, which stands for the Encyclopedia of DNA Elements. In conjunction with the release of those results, the Journal of Biological Chemistry published a thematic minireview series entitled “Results from the ENCODE Project: Integrative global analyses of regulatory regions in the human genome,” that focuses on several aspects of the findings.
“The ENCODE project not only generated an enormous body of data about our genome, but it also analyzed many issues to better understand how the genome functions in different types of cells. These insights from integrative analyses are really stories about how molecular machines interact with each other and work on DNA to produce the proteins and RNAs needed for each cell to function within our bodies,” explains Ross Hardison of Pennsylvania State University, one of the JBC authors.
Hardison continued, “The Journal of Biological Chemistry recognized that the results from the ENCODE project also would catalyze much new research from biochemists and molecular biologists around the world. Hence the journal commissioned these articles not only to communicate the insights from the papers now being published but also to stimulate more research in the broader community.”
The ENCODE research and developed technologies have generated a deeper understanding of gene enhancers. Gabriel Zentner and Peter Scacheri describe trends in histone modification at enhancer regions that enable their classification in “The chromatin fingerprint of gene enhancer elements.” For example, enhancers linked to high amounts of gene expression have a particular set of histone modifications, while enhancers associated with the transcription of noncoding RNA or with low amounts of gene expression have different, specific histone modifications. The review also discusses variant histones (H2A.Z and H3.3) in enhancer regions and enhancer binding proteins.
Michael Snyder and colleagues discuss the prototypical ATP-dependent chromatin remodeler switch/sucrose nonfermentable in “SWI/SNF chromatin remodeling factors: multiscale analyses and diverse functions.” The review focuses on human SWI/SNF — the varied combinations of SWI/SNF subunits, the ability of SWI/SNF to form DNA loops and allow the interaction of chromatin regions separated by various distances, and the role of SWI/SNF in cancer and viral infection.
The ENCODE findings also have provided insight into long-range chromatin interactions involving the transcription factor CTCF. Bum-Kyu Lee and Vishwanath Iyer report on CTCF — its various functions and the putative mechanisms by which these are accomplished — in “Genomewide studies of CTCF and cohesin provide insight into chromatin structure and regulation.” A particular area of focus is the interaction of CTCF and the cohesin protein complex.
Victor Jin and co-workers report the recent advancements in experimental and computational methods for the analysis of transcription factor modules in “Uncovering transcription factor modules using one-dimensional and three-dimensional analyses.” Among the experimental methods described are chromatin immunoprecipitation-sequencing, or ChIP-seq, which maps transcription factor binding sites with high resolution and sensitivity; chromatin interaction analysis with paired-end tag sequencing, or ChIA-PET, which detects chromatin interactions of a specific transcription factor throughout the whole genome; and Hi-C, which profiles all chromatin interactions across the genome. Computational platforms for identifying transcription-factor binding sites, chromatin interactions and transcription-factor groups are also discussed.
The ability to convert one cell type to another has great therapeutic potential. While many questions are unanswered in this area of research, recent studies provide insight into the mechanisms that regulate cell fate. These are discussed in the minireview “Transcription factor mediated epigenetic reprogramming” by Alexander Meissner and colleagues. The authors highlight the induction of somatic cells into pluripotent cells and discuss the regulation of this process via histone modification, changes in DNA methylation and regulation of specific kinases. They also compare and contrast embryonic stem cells and induced pluripotent stem cells.
Large-scale, consortium efforts such as the ENCODE project and the NIH Roadmap Epigenomics Mapping Program have produced genomewide epigenetic datasets from various types of human cells and tissues that can be used to predict regions of gene regulation. Hardison discusses the application of these data to investigate susceptibilities to common diseases that are affected by SNPs at multiple genetic loci (such as type 2 diabetes, Crohn’s syndrome and many types of cancer) in “Genome-wide epigenetic data facilitate understanding of disease susceptibility association studies.” The review provides examples of how the epigenetic datasets generated to date have been used in combination with data from genomewide association studies to determine the functional effect of disease-associated variants.
The effort behind the ENCODE project was extraordinary. More than 440 scientists in 32 labs around the world performed more than 1,600 sets of experiments on 147 types of tissue. “The deeper knowledge of gene regulation coming from the ENCODE project will have a positive impact on medical science,” Hardison emphasizes.
The JBC thematic series was organized by Peggy J. Farnham of the University of Southern California. Farnham is also an author on the main integrative ENCODE paper in Nature, as were seven other JBC authors, including Vishwanath R. Iyer, Bum-Kyu K. Lee, Raymond K. Auerbach, Ghia Euskirchen, Victor X. Jin, Hardison and Michael Snyder.
View and download the JBC reviews at http://www.jbc.org/site/thematics/encode/index.xhtml.
Visit the ENCODE project portal, www.encodeproject.org, for more information.
Danielle Gutierrez (firstname.lastname@example.org) is a freelance science writer based in Corpus Christi, Texas.