David (Dave) Allis was a pioneer in the biology of chromatin, the complex of protein and nucleic acid that makes up chromosomes. He revealed how modifications to it, specifically chemical changes to the histone proteins around which DNA wraps, affect gene expression and many other fundamental aspects of cellular function. His ‘histone code’ hypothesis suggested that other proteins read histone modifications, which are important for almost every process in eukaryotic cells that uses DNA as a template. Allis played a major part in elucidating how epigenetic changes — those beyond the genome — can affect human health and disease, suggesting entirely new avenues for therapy development. He has died aged 71.
Histone modifications were first reported by Vincent Allfrey in 1966, but before Allis’s work, their significance and associated enzyme activities remained unclear. Allis showed that they had a direct link with the regulation of DNA’s transcription into RNA and hence into expressed proteins. His work illuminated how the cell establishes and maintains patterns of gene expression, and laid the groundwork for understanding how a single genome can generate cells of many types. He received the Canada Gairdner International Award, the Breakthrough Prize in Life Sciences and the Albert Lasker Award for Basic Medical Research (with Michael Grunstein).
Allis was born in Cincinnati, Ohio, in 1951, and earned a PhD in biology from Indiana University Bloomington. During postdoctoral training with Martin Gorovsky at the University of Rochester, New York, he studied the freshwater protozoan Tetrahymena, a model organism that he carried into his independent research at Baylor College of Medicine in Houston, Texas. Allis set out to identify enzymes that add acetyl groups to histones (histone acetyltransferases, or HATs), reasoning that Tetrahymena, which has many acetylated histones, would be an excellent source of them. This decision demonstrated his knack for pursuing a unique line of inquiry with deliberation and commitment, which would prove pivotal in making significant advances.
His major breakthrough came in 1996, with his discovery of the enzyme GCN5, which acts to promote transcription, as a HAT (J. E. Brownell et al. Cell 84, 843–851; 1996). No histone-modifying enzymatic activity had yet been identified, and no data indicated that transcription machinery might include such activity. The impact of Allis’s discovery was immediate and immense, leading to an explosion in papers on HATs. The importance of histone acetylation in transcriptional regulation is now unquestioned.
Allis also had a pivotal role in defining the cause-and-effect relationship between specific modifications and gene expression. His work, more than that of any other, sparked a renaissance in the study of gene regulation through chromatin structure.
Allis settled at the Rockefeller University in New York City in 2003, after appointments at Syracuse University in New York, the University of Rochester and the University of Virginia in Charlottesville. He went on to describe the role of histone modifications beyond acetylation, including a connection between histone phosphorylation and the segregation of chromosomes during cell division. He and his collaborators uncovered a link between histone mutations and chromatin changes associated with malignant cancers. He was quick to recognize the clinical significance of this, and to note that similar mutations might alter global chromatin states in other illnesses. His work will prove essential in unravelling complex aspects of many diseases and providing new treatments.
Allis had an infectious enthusiasm for science, and he influenced the course of discovery well beyond his own laboratory. He welcomed new ideas and shared tools and expertise that fostered major discoveries by others, such as the identification of histone methyltransferase enzymes and the discovery that site-specific histone methylation patterns define chromatin domains as ‘open’ (accessible to gene transcription machinery) and ‘closed’ (relatively inaccessible). For example, histone H3 turned out to perform two opposite functions depending on the methylation states of two lysine residues only a few amino acids apart, which are read by specific protein ligands. This provided crucial evidence for the existence of the histone code (B. D. Strahl and C. D. Allis Nature 403, 41–45; 2000). Allis’s paper on this hypothesis has now been cited more than 6,000 times.
Allis was known for his warmth, creativity and humour. In accepting his many honours, he showed huge appreciation for his lab members and the community of colleagues and collaborators, citing them as the inspiring force behind his own success. He cherished his family, crediting the support of his wife Barb with his accomplishments, and proudly sharing pictures of his children and grandchildren.
He celebrated colleagues around the globe by sending them quirky, treasured mementos to honour their findings, among them hats decorated with HAT modifications, or cartoons such as one that invoked iconic cereal box-covers featuring Olympians, tweaked to celebrate the discovery of differential histone methylation patterns specifying distinct gene expression states. We end by saying to him what he often said to others to recognize major achievements: “Good show!” We miss you, Dave.