Abstract: Series 114, Lecture 1

The Harvey Lectures Series 114 (2018—2019)

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Lecture #1: Thursday, October 18, 2018 — Time and Location

Dissecting Molecular Mechanisms of Transcription Regulation

John T Lis, PhD

John T Lis, PhD

Professor in the Department of Molecular Biology and Genetics

Cornell University

Ithaca, New York

Dr Lis's Website

RNA Polymerase II (Pol II) is the highly regulated molecular machine that transcribes all mRNA encoding genes. Different sets of genes are modulated by cellular signals occurring in response to normal development, as well as to changes in nutrition and stress. Heat shock or stress response genes are a robust model system to investigate molecular mechanisms of gene regulation. Heat shock rapidly up-regulates transcription of hundreds and down-regulates thousands of genes. Our early studies revealed surprisingly that Pol II was already present on major heat shock genes prior to heat shock in a promoter-proximal paused state. These and subsequent studies showed release of paused Pol II to productive elongation was a key regulated step. More recently our genome-wide, nuclear run-on assays that map all transcriptionally-active Pol II at base-pair resolution, showed pausing to be a general feature of promoters in Drosophila and humans and provided insights to the underlying mechanisms. Specific transcription factors, such as GAGA Factor, are required to generate the promoter-proximal paused Pol II; while HSF1, which upon heat shock binds to promoters and enhancer, is in turn required to release this paused Pol II into productive elongation. These studies indicate that the action of distinct transcription factors at separate steps in the transcription cycle allows integration of different cell signaling pathways and the production of highly regulated patterns of gene expression.