Summary:
For decades that central dogma stated that information flowed from DNA to proteins via translation. In this process RNA was considered to be a passive participant simply shuttling the genetic code from the chromosome to the ribosome. However, emerging studies have discovered a great number of biological processes in which RNA plays an active regulatory role. For example, so-called micro-RNAs which are typically only 22 bases and do not code for a protein, have been shown to directly influence gene expression by ‘silencing’ target mRNAs. At another level, RNA can be chemically modified post-transcriptionally. This process, called epitranscriptomics in analogy to post-translational modification of protein and DNA known as epigenetics, alters the functional behaviour of modified RNAs. In the last 5 years, work from the laboratories of the two speakers has begun to elucidate the role and mechanism of transformation of a healthy cell to a diseased one when specific RNA modifications become misregulated.

Based upon the insights of our two speakers, amongst others, numerous companies have been launched whose goal is to develop small molecule inhibitors of misregulated epigenetic processes. Biotechs such as Storm Therapeutics, 28-7, Gotham Therapeutics and Accent Therapeutics amongst many others, are all making headlines in this space…and big pharma has taken notice. Targetting both RNA and the proteins that interact with it has become one of the hottest new areas in drug discovery. Here we will bring you two key opinion leaders who will share their insights into the mechanisms of epitranscriptomics and its relationship to disease, in particular oncology. They will describe their latest findings on important targets and the biological outcome of inhibiting them. In addition, ZoBio will share a case study on development of small molecule inhibitors of an epitranscriptomic target. In all, the webinar will bring you insights into the field, the prospects for drug discovery and what it takes to be successful if you chose to pursue it.

Professor Richard Gregory’s lab has been one of the pioneers in the field of RNA methylation and its role in leading to the disease state upon misregulation. In his talk he will discuss recent results from his laboratory relating the enzymes that perform RNA methylation and the consequences for the cell when they are misregulated.

Professor Samie Jaffrey’s lab has focused on the role of m6A methylation in translation of mRNA. His lab has developed technology to map this modification in the cellular transcriptome and defined many of the so-called writers, readers and erasers in the process. Here he will discuss the YTHDF family of readers that selectively recognize m6A mRNA and their role in leukemia and describe requirements for effective small molecule intervention.

We hope you are as excited about this webinar as we are.

Learning Objectives:

The attendee should gain deeper insight into:

• The concept of epitranscriptomics and the biological role of chemical modification of RNA.
• A sense of the range of different RNA modifications that are thus far known.
• A sense of the variety of biological functions that RNA modification regulates.
• Insight into various mechanisms by which disruption of epitranscriptomic function leads to the disease state.
• The mechanism and role of m6A modification in mRNA life cycle.
• The role of m6A modification in cellular transformation and potential mechanisms through which this process may be inhibited.
• Insight into various mechanisms to interfere in cellular transformation with small molecules.
• A better understanding of the technology and assays needed to probe the cellular function of epitranscriptomics and upon which drug discovery processes can be based.

Speakers:

Prof. Richard Gregory
Professor, Department of Pediatrics Stem Cell Biology Chair, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Affiliation: The Stem Cell Program, Division of Hematology/Oncology at Boston Children's Hospital

Richard I. Gregory, Ph.D. is Professor in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, and the Department of Pediatrics Stem Cell Biology Chair. He is principal investigator in the Stem Cell Program, Division of Hematology/Oncology at Boston Children’s Hospital. He is also co-Director and executive committee member of the Harvard Initiative for RNA Medicine, faculty member of the Dana–Farber/Harvard Cancer Center, and principal faculty member of The Harvard Stem Cell Institute. The laboratory’s research on RNA regulatory mechanisms has led to several breakthrough findings and is funded in part by an ‘outstanding investigator’ R35 award from the National Cancer Institute. Current research is focused on RNA modifications, the so-called ‘epitranscriptome’ in cancer biology. Of particular relevance are our recent findings that provide insight into the role and mechanism of the N6-methyladenosine (m6A) methyltransferase (MTase) METTL3 in the control of mRNA translation, and the first evidence that METTL3 is dysregulated in cancer and can function as an oncogene to promote cellular transformation and tumorigenesis. These early insights paved the way for the emergence of the epitranscriptome and cancer field and represent the basis for our ongoing efforts to elucidate the molecular and cellular mechanisms of the epitranscriptome in cancer and to identify pharmacological MTase inhibitors towards the development of new drugs targeting the epitranscriptome as a cancer therapy. Dr. Gregory is a scientific co-founder and scientific advisory board member of Twentyeight-Seven Therapeutics a biotechnology company that is developing cancer drugs targeting RNA pathways.

Prof. Samie R. Jaffrey, M.D., Ph.D.
Greenberg-Starr Professor of Pharmacology, Affiliation: Weill Cornell Medicine, New York, NY

Dr. Samie Jaffrey is the Greenberg-Starr Professor in the Department of Pharmacology at the Weill Cornell Medical College. Dr. Jaffrey’s work has fundamentally advanced our understanding of RNA biology and gene regulation. Most recently, he helped to launch the field of “epitranscriptomics,” which has revealed that mRNA and long noncoding RNAs are regulated by nucleotide modifications that impact their fate and function in cells. Dr. Jaffrey’s transcriptome-wide mapping of N6-methyladenosine (m6A) in 2012 revealed that m6A is a pervasive modification in the transcriptome, thereby identifying this modification as a fundamentally novel form post-transcriptional mRNA regulation. Since this seminal study, Dr. Jaffrey mapped dimethyladenosine (m6Am) and established functions of m6A and m6Am as well as m6A and m6Am reader, writer, and eraser proteins. The mapping methods developed by Dr. Jaffrey has been the essential tool in epitranscriptomics, and has transformed our understanding of gene regulation in normal and disease states. Dr. Jaffrey’s is an elected member of the American Society for Clinical Investigation, and the recipient of the 2017 John J. Abel Award in Pharmacology, the 2014 American Society for Biochemistry and Molecular Biology, the Young Investigator Award Klingenstein Neuroscience Award, Irma T. Hirschl Scholar Award, the McKnight Foundation Technology Development Award, NIH EUREKA Award, the NIH Director’s Transformative R01 Award, and the 2013 Blavatnik Award for Young Scientists.

Moderator:

Dr. Gregg Siegal
ZoBio