Impact of the Functionalized Genome on NIAMS Diseases – Implications from ENCODE

1. NIAMS Extramural Scientific Planning Retreat 2013April 4, 2013Session 3: Impact of the Functionalized Genome on NIAMS Diseases – Implications from ENCODE

2. Impact of the Functionalized Genome on NIAMS Diseases – Implications from ENCODE • Goals: • Gain a better understanding of the opportunities enabled by the Encyclopedia of DNA Elements (ENCODE) • Discuss strategies to overcome challenges and facilitate leveraging of the ENCODE resources to advance NIAMS research • Guest Speakers from National Human Genome Research Institute (NHGRI): • Dr. Teri Manolio • Dr. Elise Feingold • Dr. Michael Pazin

3. Encyclopedia of DNA Elements (ENCODE) • International Public Research Consortium • Launched by National Human Genome Research Institute (NHGRI) in September 2003 • Goal is to build a comprehensive parts list of functional elements in the human genome, including • Elements that act at the protein and RNA levels, and • Regulatory elements that control cells and circumstances in which a gene is active • Today, ENCODE has begun to transform the interpretation of Genome Wide Association Studies

4. Encyclopedia of DNA Elements (ENCODE) “During the early debates about the Human Genome Project, researchers had predicted that only a few percent of the human genome sequence encoded proteins, and that the rest was junk. We now know that this conclusion was wrong. ENCODE has revealed that most of the human genome is involved in the complex molecular choreography required for converting genetic information into living cells and organisms.” -- Eric D. Green, M.D., Ph.D., Director of the National Human Genome Research Institute (NHGRI)

5. Encyclopedia of DNA Elements (ENCODE) Ecker et al.Nature. 2012. 489(7414): 52.

6. Encyclopedia of DNA Elements (ENCODE) • As much as 80% of the non-coding genome may be functional (i.e., participates in at least one biochemical RNA- and/or chromatin-associated event in at least one cell type). • Patterns of active elements are tissue- and cell-type-specific. • Many disease-associated polymorphisms (GWAS “hits”) are found in or near functional elements. • Targets of regulatory elements are not necessarily the nearest genes. Disease-associated elements imply regulatory networks, illuminating pathophysiology.

7. Encyclopedia of DNA Elements (ENCODE)—Opportunities • Generate genome-wide ENCODE-type data from cells and tissues that are directly relevant to rheumatic, skin, and musculoskeletal diseases • Integrate these data with the data and analytical resources produced by the original ENCODE investment • Stimulate active collaborations between • Investigators experienced in the study of NIAMS-specific diseases and tissues, and • Investigators experienced in the genome-wide analysis of biochemical features such as DNase hypersensitivity, DNA methylation, histone modification, and bioinformatics experts Involvement of NHGRI staff and investigators with direct experience in the ENCODE data pipeline will be valuable in ensuring that these new data are compatible with the quality control and formatting standards established by ENCODE.