Non-coding RNAs in Oncogenesis

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Non-coding RNAs in Oncogenesis

Tuesday, November 16, 2010

The New York Academy of Sciences

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Non- coding RNAs are emerging as important regulators of development and function in many physiological processes. Their role in controlling pathogenesis and their potential as targets for therapeutic intervention are becoming increasingly apparent.

Networking reception to follow.

Sponsors


This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.

Agenda

*Presentation times are subject to change.


12:30 PM

Registration

1:00 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Senthil Muthuswamy, PhD, Cold Spring Harbor Laboratory

1:10 PM

miRNAs in Breast Cancer
Greg Hannon, PhD, Cold Spring Harbor Laboratory

1:50 PM

The ceRNA Hypothesis, the Non-coding Revolution and the Future of Cancer Research and its Therapy
Pier Paolo Pandolfi, MD, PhD, Harvard Medical School

2:30 PM

Long Non-Coding RNAs Involved in Nuclear Organization and Function
David Spector, PhD, Cold Spring Harbor Laboratory

3:10 PM

Coffee Break

3:40 PM

Large Intergenic Non-coding RNAs: From Discovery to Mechanism
John L. Rinn, PhD, Harvard Medical School

4:20 PM

Long Non-coding RNAs with Enhancer-like Function
Ramin Shiekhattar, PhD, The Wistar Institute

5:00 PM

Networking Reception

Speakers

Organizers

Senthil K. Muthuswamy, PhD

Cold Spring Harbor Laboratory and Ontario Cancer Institute, Toronto

Dr Muthuswamy received his PhD with William Muller in Biology from McMaster University, Hamilton, Canada and did his postdoctoral fellowship with Joan Brugge at Harvard Medical School. He began his independent faculty position at Cold Spring Harbor Laboratory, New York and now at Ontario Cancer Institute and Campbell Family Institute for Breast Cancer Research as the Margaret Lau Chair in Breast Cancer Research. He is a recipient of Rita Allen Scholar award, V Foundation scholar award, the US Army Era of Hope Scholar Award, and CSBMCB young investigator award (formerly Merck-Frost Prize). Dr Muthuswamy’s research goal is to understand the how cell polarity pathways regulate epithelial cell morphogenesis, differentiation and tumorigenesis. Research from his laboratory has demonstrated that oncogenes interact with polarity proteins to disrupt apical-basal polarity and to transform polarized breast epithelial structures. The ability of oncogenes to disrupt cell polarity is independent of their ability to induce cell proliferation, suggesting that pathways that regulate cell and tissue architecture and cell proliferation are separable. More recently, they have demonstrated that disruption of polarity pathways deregulates morphogenesis of mammary epithelial cells in culture and in vivo and cooperates with oncogenes to initiate carcinoma suggesting that disruption of polarity proteins can function either as an initiating or as an cooperating event during the genesis of carcinoma. These observations provide direct evidence for a role for polarity pathways during tumorigenesis and identify them as novel targets that can be exploited for diagnosis and treatment of carcinoma.

Pier Paolo Pandolfi, MD, PhD

Harvard Medical School

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Greg Hannon, PhD

Cold Spring Harbor Laboratory

Greg Hannon is a Professor in the Watson School of Biological Sciences at Cold Spring Harbor Laboratory. He received a B.A. degree in biochemistry and a Ph.D. in molecular biology from Case Western Reserve University. From 1992 to 1995, he was a postdoctoral fellow of the Damon Runyon-Walter Winchell Cancer Research Fund, where he explored cell cycle regulation in mammalian cells. After becoming an Assistant Professor at Cold Spring Harbor Laboratory in 1996 and a Pew Scholar in 1997, in 2000, he began to make seminal observations in the emerging field of RNA interference. In 2002 Dr. Hannon accepted a position as Professor at CSHL where he continued to reveal that endogenous non-coding RNAs, then known as small temporal RNAs and now as microRNAs, enter the RNAi pathway through Dicer and direct RISC to regulate the expression of endogenous protein coding genes. He assumed his current position in 2005 as a Howard Hughes Medical Institute Professor and continues to explore the mechanisms and regulation of RNA interference as well as its applications to cancer research.

Pier Paolo Pandolfi, MD, PhD

Harvard Medical School

Pier Paolo Pandolfi received his M.D. in 1989 and his Ph.D. in 1996 from the University of Perugia, Italy, after having studied Philosophy at the University of Rome, Italy. He received post-graduate training at the National Institute for Medical Research and the University of London in the UK. He became an Assistant Member of the Molecular Biology Program and the Department of Human Genetics at Memorial-Sloan-Kettering Cancer Center in 1994. Dr. Pandolfi grew through the ranks to become a Member in the Cancer Biology and Genetics Program at the Sloan Kettering Institute; Professor of Molecular Biology and Human Genetics at the Weill Graduate School of Medical Sciences at Cornell University; Professor, Molecular Biology in Pathology and Laboratory Medicine, Weill Medical College at Cornell University; and Head of the Molecular and Developmental Biology Laboratories at MSKCC. Dr. Pandolfi was also the incumbent of the Albert C. Foster Endowed Chair for Cancer Research at Memorial Sloan-Kettering Cancer Center. Dr. Pandolfi presently holds the Reisman Endowed Chair of Medicine, and is Professor of Pathology at Harvard Medical School. He serves as the Director of Research, Beth Israel Deaconess Cancer Center; Director, Cancer Genetics Program; and Chief, Division of Genetics in the Department of Medicine, Beth Israel Deaconess Medical Center, and is a Member of the Department of Pathology, Beth Israel Deaconess Medical Center. Dr. Pandolfi has been the recipient of numerous awards including the LLSA Scholar Award (1997), the Irma T. Hirschl Trust Award (1999), the Alexandra J. Kefalides Prize for Leukemia Research (1999), the Hamdan Award for Medical Research Excellence (2000), the Lombroso Prize for Cancer Research of the Weizmann Institute of Science (2001), the Leukemia and Lymphoma Society’s Stohlman Scholar Award (2001); the William and Linda Steere Foundation Award (2004) and the prize for Scientific Excellence in Medicine from the American-Italian Cancer Foundation (2005). He also has been awarded the NIH MERIT Award for superior competence and outstanding productivity in research, the Fondazione Cortese International Award, the Prostate Cancer Foundation Creativity Award and the Ischia International Award. In 2006, Dr. Pandolfi was elected as a member of the American Society for Clinical Investigation (ASCI) and the American Association of Physicians (AAP), and in 2007 as Member of the European Molecular Biology Organization (EMBO). The research carried out in Dr. Pandolfi’s laboratory has been seminal to elucidating the molecular mechanisms and the genetics underlying the pathogenesis of leukemias, lymphomas and solid tumors as well as in modeling these cancers in the mouse. Dr. Pandolfi and colleagues have characterized the function of the fusion oncoproteins and the genes involved in the chromosomal translocations of acute promyelocytic leukemia (APL), as well as of major tumor suppressors such as PTEN and p53, and novel proto-oncogenes such as POKEMON. The elucidation of the molecular basis underlying APL pathogenesis has led to the development of novel and effective therapeutic strategies. As a result of these efforts, APL is now considered a curable disease. Additional novel therapeutic concepts have emerged from this work and are currently being tested in clinical trials. More recently, Dr. Pandolfi and colleagues have presented a new theory describing how mRNA, both coding and non coding, exerts their biological functions with profound implications for human genetics, cell biology and cancer biology.

John L. Rinn, PhD

Harvard Medical School

John is a senior-associate member of the Broad Institute and assistant professor of Stem Cell and Regenerative Biology at Harvard University. John’s graduate research was one of the first to discover an abundance of RNA molecules emanating from non-coding, often referred to as ‘junk regions’ of the human genome. He continued to pursue these mysterious RNA molecules for his postdoctoral work leading to the discovery of a novel type of non-coding RNA, termed HOTAIR, encoded on one chromosome that silences a large region on a different chromosome. This work also revealed a genetic code of large non-coding RNAs and HOX genes that determine the localization of an adult human skin cell in the body, similar to the way a GPS system locates a person’s position on earth (latitude, longitude and altitude), in this case by triangulation of three genetic axes. Inspired by HOTAIR the Rinn lab developed a novel approach to hone in one functional RNA molecules. This led to a recent discovery of a class of large intergenic non-coding RNAs (lincRNAs); perhaps are ‘missing lincs’ in genome regulation. LincRNAs are involved in numerous key biological processes such as the cellular transformation to cancer and embryonic stem cell pluripotency. Now their goal is to understand the mechanisms of large non-coding RNA in establishing and maintaining these distinct epigenetic states of adult and embryonic cells and how misregulation of their identity results in cancer. By exploiting multiple high-throughput genomic technologies they are actively discovering and functionally characterizing an abundance of these elusive molecules throughout the human and mouse genomes. Ultimately, they aim to utilize large non-coding RNAs that act in trans to target and silence oncogenes in cancer.

Ramin Shiekhattar, PhD

The Wistar Institute

Ramin Shiekhattar is a Professor of Gene Expression and Regulation program at Wistar Institute and hold the Herbert Kean Professorship. He received a B.S. degree in chemistry and a Ph.D. in biochemistry from University of Kansas. He was a postdoctoral fellow (1993-1996) obtaining the National Research Service Award (NRSA) to investigate the mechanism of eukaryotic transcription in human cells. Dr. Shiekhattar joined the faculty of the Wistar Institute in 1997 as an assistant professor and began his seminal contributions to the filed of epigenetics through biochemical characterization of chromatin modifying as well as RNA processing complexes. These include the identification of BRCA1-associated complexes, novel histone demethylase complexes as well as the discovery of the RNA processing machineries such as the Microprocessor and Integrator complexes. In 2007, Dr. Shiekhattar Laboratory extended their analysis of the role of RNA in epigenetic regulation by assessing the role of long non-coding RNAs. This work has revealed that a class of long non-coding RNAs in human cells behave similar to classically defined enhancer elements and consequently begins a new chapter in the biological scope of non-coding RNAs in mammalian development.

David Spector, PhD

Cold Spring Harbor Laboratory

David L. Spector, Ph.D., is Director of Research at Cold Spring Harbor Laboratory, he has been a member of the CSHL faculty since 1985. Dr. Spector’s research centers on understanding the organization and regulation of gene expression in living cells. His laboratory’s work is focused on implementing innovative approaches to elucidate the spatial and temporal aspects of gene expression and in identifying and characterizing the function of nuclear retained long non-coding RNAs. An expert in microscopy, Dr. Spector also directs the Microscopy Shared Resource at CSHL. He has edited numerous microscopy techniques manuals that are used in laboratories throughout the world and he serves on the editorial boards of Journal of Cell Science, Epigenetics & Chromatin, and Current Opinion in Cell Biology. He has also been elected to the Council of the American Society of Cell Biology. In 2006 he received the Winship Herr Award for Excellence in Teaching from the Watson School of Biological Sciences.

Sponsors

For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.

This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.

Grant Support

This event is funded in part by the Life Technologies™ Foundation.

Abstracts

miRNAs in Breast Cancer

Greg Hannon, PhD, Cold Spring Harbor Laboratory

 

The ceRNA Hypothesis, the Non-coding Revolution and the Future of Cancer Research and its Therapy

Pier Paolo Pandolfi, MD, PhD, Harvard Medical School

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. Here we present a hypothesis whereby mRNAs exert an unseen function that relies on their ability to communicate with one another (by competing with other RNA transcripts for cellular microRNAs) through microRNA recognition sequences (MREs) as words of a new “RNA language”. Because this function does not rely on the genetic blueprint that RNA harbors within its protein-encoding nucleotide sequence, our discovery extends to most of the entire cellular transcriptome, protein coding or not. This encompasses all coding genes, several thousand pseudogenes, and the growing family of large non-coding RNAs (lncRNA). We term RNA species in this context as ceRNA, for competing endogenous RNA. This phenomenon expands the total collection of functional genetic information in our genome and attributes a novel and bioinformatically predictable function to ceRNAs, thus implicating these largely uncharacterized genetic entities in physiological processes and pathological conditions. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumor suppressor gene and its pseudogenes PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.

Large Intergenic Non-coding RNAs: From Discovery to Mechanism

John L. Rinn, PhD, Harvard Medical School

A fundamental and unsolved problems in biology is: how does the same genome present in every cell encode a multitude of different cellular states? It is well established that epigenetic regulation plays a key role in this process, yet the array of these epigenetic landscapes are established by ubiquitously expressed chromatin remodeling complexes. It has long been suspected that non-coding RNA molecules to bring these complexes to their sites of action. Indeed, we and others have recently discovered several examples of large non-coding RNA molecules that ‘guide’ chromatin formation. Interestingly, these known examples (e.g. XIST, HOTAIR, and AIR) confer distinctive epigenetic states, yet share a common mechanism: they physically associate with chromatin remodeling complexes and ‘guide’ them to specific genomic loci. Here we show that large ncRNAs may be a general mechanism for the establishment and maintenance of epigenetic states in development and disease. We recently discovered a new class of highly conserved large intergenic non-coding RNAs (lincRNAs) and a computational method to predict their functions. This “guilt by association method” pointed to a clear association of lincRNAs with chromatin remodeling complexes, particularly in the context of cancer and pluripotent cell states. Here, we present a systematic and comprehensive approach that demonstrates a majority of lincRNAs associate with various chromatin-remodeling complexes and regulate specific genomic sites in cancer and the derivation of induced pluripotent stem cells. As one example, we show that p53 directly and temporally induces several lincRNAs in response to DNA damage. Including lincRNA-p21 that is required for proper localization of chromatin factors to mediate p53 dependent cellular apoptosis. Together, these results point to key regulatory roles for lincRNAs across diverse biological pathways, through interfacing with and imparting specificity to chromatin modifying remodeling complexes.

Long Non-coding RNAs with Enhancer-like Function

Ramin Shiekhattar, PhD, The Wistar Institute

While the long non-coding RNAs (ncRNAs) constitute a large portion of the mammalian transcriptome, their biological functions has remained elusive. A few long ncRNAs that have been studied in any detail silence gene expression in processes such as X-inactivation and imprinting. We used a GENCODE annotation of the human genome to characterize over a thousand long ncRNAs that are expressed in multiple cell lines. Unexpectedly, we found an enhancer-like function for a set of these long ncRNAs in human cell lines. Depletion of a number of ncRNAs led to decreased expression of their neighboring protein-coding genes, including the master regulator of hematopoiesis, SCL (also called TAL1), Snai1 and Snai2. Using heterologous transcription assays we demonstrated a requirement for the ncRNAs in mediating such enhancement of gene expression. These results reveal an unanticipated role for a class of long ncRNAs in activation of gene expression.

Long Non-Coding RNAs Involved in Nuclear Organization and Function

David Spector, PhD, Cold Spring Harbor Laboratory

The cell nucleus is a highly compartmentalized organelle harboring a variety of dynamic membraneless nuclear bodies. How these subnuclear domains are established and maintained is not well understood. We have investigated the molecular mechanism of how one nuclear body, the paraspeckle, is assembled and organized. Paraspeckles are discrete ribonucleoprotein bodies found in mammalian cells and implicated in nuclear retention of hyperedited mRNAs. We have found that Men ε/ß (also known as Neat1) non-coding (nc) RNAs are localized to paraspeckles and are upregulated upon the differentiation of myoblasts to myotubes. We developed a live-cell imaging system that allows for the inducible transcription of Men ε/ß and the direct visualization of the recruitment of paraspeckle proteins. Using this system, we demonstrate that Men ε/β ncRNAs are essential to initiate the de novo assembly of paraspeckles. These newly formed structures effectively harbor nuclear retained mRNAs confirming that they are bona fide functional paraspeckles. By three independent approaches, we show that it is the act of Men ε/βtranscription, but not ncRNAs alone, that regulates paraspeckle maintenance. Finally, FRAP analyses support a critical structural role of Men ε/β ncRNAs in paraspeckle organization. Together, these findings establish a model in which ncRNAs can serve as a platform to recruit proteins to assemble a nuclear body.

* Additional abstracts coming soon.

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