IEEE BIBM 2020 Workshop on Long Non-Coding RNAs: Mechanism, Function, and Computational Analysis (BIBM-LncRNA)

The non-protein coding portions of the human genome, or the noncoding genome, is a bizarre, confusing and exciting aspect of our genetic template. The sequencing of the human genome opened the wardrobe to Narnia, filled with fascinating new regulatory elements and molecular modalities. Here we will discuss our journey into “noncodarnia” and what we have found in the wardrobe over the past 15 years.

John Rinn - Leslie Orgel and Marvin Caruthers Professor of RNA Science at the University of Colorado Boulder. In late 2017, John Rinn moved from Harvard University and the Broad Institute to the University of Colorado Boulder. His laboratory aims to understand how the noncoding (non protein coding) genome regulates development and disease. This led to early discoveries that the genome encodes a mysterious class of RNA genes termed long noncoding RNAs (lncRNA). The Rinn laboratory research has spent decades identifying and mapping lncRNA loci across many species with a parallel goal of assessing how these newly identified lncRNAs contribute to cellular and organismal phenotypes.

Prior to CU Boulder, John Rinn served as a tenured professor at Harvard University. The previous research by the Rinn laboratory at was carried out at Harvard University department of Stem Cell and Regenerative Biology (HSCRB), the Broad Institute and Beth Israel Deaconess Medical Center (BIDMC) at Harvard Medical School. This genome wide research honed in on a small set of lncRNAs that exhibit bona fide RNA based mechanisms and some with genetic associations to human disease.

These findings culminated in the need to understand a new a fundamental question: how do these "RNA Machines" work on a molecular level?

It was this question that lead the Rinn lab to move from Harvard to CU Boulder. In addition to research Professor Rinn has a long standing passion for teaching with development of graduate level RNA genomics courses to sophomore biology at Harvard that blends the fundamentals of biology with modern genomic approaches. This was another motivation to move to CU Boulder BioFrontiers that is based in integrative biology and an exciting new approach to graduate school education.

John Rinn earned his bachelor’s degree in chemistry from the University of Minnesota. He graduated cumma sum laude with department honors, earned the 1999 Casmir Ilenda Award for the university’s best senior thesis research and presentation. He went on to obtain his doctoral degree in biophysics and biochemistry from Yale University, where earned the 2008 Damon Runyon Cancer Foundation Postdoctoral Scholarship with Howard Chang at Stanford University.

Tumours evolve through somatic mutations that enable cells to replicate uncontrollably and invade new sites. Genes carrying these “driver” mutations are prime therapeutic targets, and hundreds of protein-coding driver genes have been identified through targeted sequencing of their exons. Unfortunately, the lack of entire tumour genome sequences has made it impossible to search for driver elements in the noncoding genome, including the many thousands of long noncoding RNAs (lncRNAs). Very recently, this has been solved by the International Cancer Genome Consortium’s “PCAWG” (Pan Cancer Analysis of Whole Genomes) project, which has comprehensively mapped mutations across >2500 tumour genomes. We have developed a bioinformatic pipeline, ExInAtor2, which identifies candidate driver lncRNAs using integrated signatures of positive evolutionary selection. Applying ExInAtor2 to thousands of primary and metastatic tumour genomes, we present a panorama of driver lncRNAs across multiple cancer types. Candidate driver lncRNAs have a series of suggestive and statistically-significant features of genuine disease genes. To further test the notion that lncRNAs can behave as driver genes, we employ CRISPR-Cas9 to directly assay the phenotypic effects of mutations. In summary, analysis of whole tumour genomes opens new vistas in therapeutically targeting lncRNAs.

Rory Johnson received his MSc in Physics and Biophysics from Imperial College in London. Following a PhD thesis on gene regulation in the nervous system, he performed postdoctoral work at the Genome Institute of Singapore, where he learned next generation sequencing and bioinformatics techniques, and became interested in the nascent field of long noncoding RNAs. He moved to the group of Roderic Guigó at the Centre for Genomic Regulation (Barcelona), where he won a Ramón y Cajal fellowship and worked with the GENCODE consortium to develop annotations of long noncoding RNAs. In 2016 he became a Junior PI with the Swiss Centre for Competence in Research “RNA & Disease” and founded the Genomics of Long noncoding RNAs and Disease (GOLD Lab), which is dedicated to developing new therapies based on long noncoding RNAs. In 2019 he was awarded a Future Research Leaders programme grant by Science Foundation Ireland to establish a research programme in CRISPR, cancer and long noncoding RNAs at University College Dublin. More information can be found at www.gold-lab.org

Cancers result from a set of genetic and epigenetic alterations. Most known oncogenes were identified by gain-of-function mutations in cancer. While could be achieved by analyzing the alternation of protein sequence coded by mRNA, such analysis is hard for lncRNA that does not code protein. We discover broad genic repression domains (BGRD) on chromatin as an epigenetic signature for oncogenes. A BGRD is a widespread enrichment domain of the repressive histone modification H3K27me3 and is further enriched with multiple other repressive marks including H3K9me3, H3K9me2, and H3K27me2. Further, BGRD displays widespread enrichment of repressed cis-regulatory elements. Shortening of BGRDs is linked to derepression of transcription. BGRDs at oncogenes tend to be conserved across normal cell types. Putative tumor-promoting genes and lncRNAs defined using BGRDs are experimentally verified as required for cancer phenotypes of tumor cells. Therefore, BGRDs play key roles in epigenetic regulation of cancer and provide a direction for mutation-independent discovery of oncogenes.

Dr. Chen is a computational biologist interested in computational modeling of cell identity regulation and tumorigenesis. He received PhD degree from the renowned Beijing Institute of Genomics. Thereafter, he joined the Dan L Duncan Cancer Center at Baylor College of Medicine as a postdoctoral fellow. Dr. Chen started his bioinformatics lab as an Assistant Professor in the Cornell University Weill Cornell Medical College at Houston Methodist Hospital, where he further became an Associate Professor and was designated as the founding Director to develop a Center for Bioinformatics and Computational Biology. Dr. Chen is currently an Associate Professor in the Harvard Medical School at Boston Children’s Hospital.