Abstract: Series 115, Lecture 1

The Harvey Lectures Series 115 (2019—2020)

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Lecture #1: Thursday, October 17, 2019 — Watch Video of Lecture

Modifying my career in pursuit of histone secrets: a tale about tails and more

C David Allis, PhD

C David Allis, PhD

Joy and Jack Fishman Professor & Head of the Laboratory of Chromatin Biology and Epigenetics

The Rockefeller University

New York, New York

Dr Allis's Website

A brief personal and historical perspective will be presented leading to the general view that the regulation of the enzyme systems responsible for adding (‘writers’) or subtracting (‘erasers’) post-translational modifications from histones and DNA, or for reading them (‘readers’), are taking center stage in the study of cancer in the current post-genomic or epigenomic era. In support, two general areas will be discussed: 1) studies focusing upon a chromatin ‘reader’ protein ENL, a conserved YEATS domain-containing protein, that is critically important for the maintenance of a broad range of acute leukemia. Recurrent mutations in the ENL YEATS domain have also been identified in a childhood kidney cancer, Wilms tumors. We hypothesize that these ENL mutations result in a gain of function in chromatin targeting and transcriptional control that ultimately drives tumorigenesis in early developing kidney, and 2) recent studies have also centered upon histone mutations (‘oncohistones’), representing a previously unrecognized mechanism to alter epigenetic states in a variety of pathologies through inhibition of a wide range of histone methyltransferases, thereby disrupting the highly coordinated epigenetic programs required for cell-specific differentiation. Publicly available as well as previously unreported institutional sequencing data were analyzed to assemble an oncohistone database. Mutations occur in all four core histones and in both the N-terminal tails and globular histone fold domains. This histone mutation database and generated hpotheses will be presented underscoring an expanding role of histone mutations in a wide range of cancer types.