School of Medicine

Wayne State University School of Medicine

Dr. Lipovich lab proving the 'junk' in between genes really matters

Leonard Lipovich, Ph.D.

Leonard Lipovich, Ph.D.

The September 2012 issue of Genome Research includes two articles featuring the work of Leonard Lipovich, Ph.D. and his lab team.

The September 2012 issue of Genome Research includes two articles featuring the work of Leonard Lipovich, Ph.D. and his lab team.

The Encyclopedia of DNA Elements project, or ENCODE, is the international research follow-up to the Human Genome Project.

The Encyclopedia of DNA Elements project, or ENCODE, is the international research follow-up to the Human Genome Project.

Dr. Leonard Lipovich’s determination to prove genetic matter once deemed “junk” has a place in clinical medicine is bringing the Wayne State University School of Medicine to the forefront of a burgeoning field occupying genome enthusiasts in the United States, Asia and Europe.

The work, on long non-coding ribonucleic acids, or lncRNAs, could lead to new therapeutics for cancer and other diseases.

“Long non-coding RNA genes comprise half of human genes. Most medical, therapeutic work so far has focused on normal, protein-coding genes. So, we – working as part of a multinational team of scientists - have just expanded, twofold, the set of genes that can be therapeutic targets,” he said.

The publication of two groundbreaking articles highlighting results from his lab at WSU’s Center for Molecular Medicine and Genetics is pushing Dr. Lipovich, and his lab’s fellow and graduate students, into the spotlight.

“For many years people pooh-poohed our field, saying that our long non-coding RNAs are either junk, or conventional protein-coding messenger RNAs that we failed to properly understand. We now demonstrate, using an experimental approach, that they are really non-protein-coding (never translated into protein) RNAs in human cells,” said Dr. Lipovich, Ph.D., assistant professor of Molecular Medicine and Genetics and of Neurology.

Dr. Lipovich is a joint last author on a paper on whole-genome translation testing of human lncRNAs, included in the September 2012 issue of Genome Research, the genetics and genomics field’s leading peer-reviewed journal. The September issue is dedicated to the latest phase of results from the Encyclopedia of DNA Elements (ENCODE) Consortium – an international human genomics effort that succeeded the completion of 2001’s Human Genome Project.

The paper sets a new standard for how to integrate RNA data with protein data in a way that has never been done. “My lab, through its computational work here at Wayne, did a vital part of the integration, developing a method that can be used in any future studies that intersect protein and RNA data genome-wide,” Dr. Lipovich said. “Unusual, rare lncRNA-encoded proteins, such as those we found, could be the results of incorrect lncRNA processing by cells in diseased tissues, and hence a huge resource of biomarkers for diagnostics.”

“Long non-coding RNAs are emerging as a huge part of primate, including human-specific, complexity or human phenotypic uniqueness. Yet, they play a critical role in regulating the conserved part of the genome,” said Emily Wood, a WSU Molecular Medicine and Genetics doctoral candidate who served as a second author on the lncRNA translation paper.

“It’s really on the edge of what’s known,” she added, calling the lncRNA field “the wild, wild West” right now.

“There is no unified model of how lncRNAs work,” she said. “We’re really interested in therapeutics in this lab. We’re also not working on a model organism. We’re looking at the activity of the human genome in actual human tissues.”

A  National Human Genome Research Institute-funded consortium, international in scope and aided by funding from several countries in Europe and Asia, ENCODE is one of the two major collaborative groups to succeed the completion of the Human Genome Project in 2001, which gave science the ability to read nature's complete genetic blueprint for building a human being.

Abnormal translation – the unusual expression of proteins from RNAs that are not supposed to be protein templates -- clearly has the potential to emerge as a key trend in cancer and autoimmunity research soon, Dr. Lipovich said, and major genomics labs at Harvard Medical School and other top universities are working on complementary aspects of this biological problem.

WSU postdoctoral fellow Hui Jia, Ph.D., in the Lipovich Lab, and WSU Molecular Medicine and Genetics doctoral candidate Will Gundling, during his rotation in the lab last year, also contributed as co-authors of the article, titled “Long noncoding RNAs are rarely translated in two human cell lines.” Dr. Jia is a joint-first author of the paper.

“The energy in the lncRNA community is phenomenal,” Wood said. “It’s a really exciting time to be part of that community. It’s not a science that’s been around forever that we can fine tune. It’s really fun to be a student and be a part of it.”

An additional paper in September’s Genome Research co-written by Dr. Lipovich, “The GENCODE catalogue of human long non-coding RNAs: Analysis of their gene structure, evolution and expression,” presents the most authoritative reference catalog of noncoding-RNA genes ever constructed.

“It will be used by the entire international ENCODE Consortium as a foundation for functional studies linking this exciting new class of RNAs to human health and disease,” said Dr. Lipovich, a middle author on this large, international effort from ENCODE’s Analysis Working Group.

The ENCODE AWG is open to all academic, government and private sector scientists interested in participating in an open process to facilitate the comprehensive identification of the functional elements in the human genome sequence, and who agree to a variety of criteria.

In the GENCODE paper, he and his colleagues found that nearly 5,000 human lncRNAs are not conserved – meaning that there are no similar or identical sequences, in species outside of primates, to these genes. These primate-specific lncRNAs are, hence, absent in mice and other animals. This highlights the limitations of animal models, and the need to study humans to understand human disease, he said. This has major implications for the molecular basis of primate and human uniqueness – which just might be encoded in part by these new RNAs, he said.

Dr. Lipovich also is a member of the Japan-based international research consortium Functional Annotation of the Mammalian Genome, the other leading post-genomic effort. FANTOM, headquartered at the RIKEN (Japan Institute of Physical and Chemical Research) Omics Science Center in Yokohama, analyzes the mammalian transcriptome -- the complete set of all RNA molecules produced in one or a population of cells – using next-generation sequencing.

For FANTOM5, he contributes computational analysis of complex loci and lncRNA network validations. Other member institutions working with RIKEN – and WSU – on this project include Harvard, University of California at Berkeley, Sweden’s Karonlinska Institutet, The Roslin Institute at the University of Edinburgh, Scotland, and the United Kingdom’s Medical Research Council. Dr. Lipovich’s RIKEN collaboration started in 2004, when he joined FANTOM3 while a postdoctoral fellow at the Genome Institute of Singapore.

“WSU earned its ENCODE AWG membership because of the world-class computational genomics that I've been doing in my lab here since 2007 – methods and results that are valued by the FANTOM Consortium in Japan and that through FANTOM exposed us to other valuable collaborators -- such as ENCODE,” Dr. Lipovich said. The Lipovich Lab is the only laboratory in the entire State of Michigan to participate in both FANTOM and ENCODE, a prestigious distinction.

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