An rna safari: exploring the surprising diversity of mammalian transcriptomes

Lectures: 1 session / week, 2 hours / session

7.03 Genetics

7.05 General Biochemistry

7.06 Cell Biology

7.08J Biological Chemistry II

One of the most fascinating aspects of mammalian biology is the use of a single DNA blueprint to create a myriad of RNA molecules that define each differentiated cell type. For many years, it was thought that RNA exists solely to do the bidding of DNA by relaying instructions for protein synthesis to the cytoplasm and aiding in translational processes. However, recent research into RNA biology has shown that RNA exists in the cell in many varied forms, each with a distinct set of cellular responsibilities. We now understand that RNAs are dynamic molecules capable of participating in a wide range of chemical reactions, from guiding the modification and processing of other RNA molecules to directing protein complex formation or silencing unwanted transposon expression. Many newly discovered RNA classes have unique capabilities and reveal surprising complexity in their compositions, lengths, and even shapes.

The aim of this class is to introduce the exciting and often underappreciated discoveries in RNA biology by exploring the diversity of RNAs—encompassing classical molecules such as ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and messenger RNAs (mRNAs) as well as newer species, such as microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). For each class of RNA we will discuss its role as a critical component of cellular machinery, its function in the context of disease, and / or its adaptation as a powerful tool in molecular biology. We will discuss the seminal studies that led to the discovery of each class of RNA, beginning with classic experiments that first identified the mRNAs, rRNAs and tRNAs as key regulators of gene expression. Given this historical perspective, we will move forward by discussing a new class of RNAs each week. As we progress, we will consider advances in techniques and equipment that have that facilitated the discovery, annotation, and analysis of new RNA molecules, with a particular focus on high-throughput sequencing and novel genomic methods.

In line with this approach, we will visit a research platform at the Broad Institute of MIT and Harvard to better understand the impact of these techniques and to meet scientists helping to further discoveries in RNA biology. Class sessions will be highly interactive and focus on the critical reading of the primary research literature to introduce important concepts in RNA biology, experimental approaches, and as-yet-unanswered questions in the field. For each new class of RNA, we will evaluate the evidence for its existence as well as for its proposed function. Students will develop both a deep understanding of the field of RNA biology and the ability to critically assess new papers in this fast-paced field.

This course will meet weekly for two hours, during which we will probe primary research papers from the scientific literature during interactive discussion. Students will be assigned two papers to be read before each class and are expected to send the instructors two questions per paper prior to the class session.

Discussions will revolve around critically evaluating the rationale supporting the experiments performed, the experimental study design, properly controlled experiments and the support for the conclusions drawn based on the data. Initially, students will be led in discussion by the instructors, but for the later sections of the course, students will be expected to be able to form arguments that support or challenge a key conclusion of the paper. At the end of each class, instructors will briefly provide the background necessary to understand the rationale and experiments of the papers to be discussed in the following week's session. Students are required to attend every class and actively contribute to the discussion.

To introduce students to the day-to-day workings of scientists at the forefront of RNA technologies and biological applications, we will visit to the Genetic Perturbation Platform at the Broad Institute of MIT and Harvard near the MIT campus in Cambridge. Students will have the opportunity to tour the facility, observe the process behind large-scale RNA technology development, and talk to researchers tackling these problems. As background, students should read the following paper from Hu and colleagues that uses a genome-wide siRNA screen to identify genes important for self-renewal in mouse embryonic stem cells.

G, Hu, J Kim, et al. "A Genome-wide RNAi Screen Identifies A New Transcriptional Module Required for Self-Renewal." Genes and Development 23, no. 7 (2009): 837-48.

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