Heads of Laboratories
Joy and Jack Fishman Professor
Laboratory of Chromatin Biology and Epigenetics
Dr. Allis studies the DNA-histone protein complex called chromatin, which packages genetic information within each cell. Chromatin can facilitate or restrict access to specific genes, enabling the cell to efficiently manage expression of its genome and serving as a means of gene regulation outside of DNA — the basis of epigenetics.
Chromatin is the physiological template of the human genome. The histone proteins within chromatin, their posttranslational modifications, and the enzyme systems responsible for generating them are highly conserved through evolution. Meanwhile, elaborate mechanisms have evolved to introduce meaningful variation into chromatin to alter gene expression and other important biological processes.
One such mechanism involves the addition or loss of chemical groups, and the Allis lab is currently investigating these covalent modifications to histones and their biological roles in a variety of unicellular and multicellular eukaryotic models. Through such enzymatic processes as acetylation, methylation, phosphorylation and ubiquitylation, histones are believed to function like master on/off switches and determine whether particular genes are active or inactive. Knowing how to turn particular genes on or off could reduce the risk of certain diseases.
The frequent, high-density posttranslational modifications (PTMs) in histone proteins has led members of the Allis laboratory to hypothesize that PTMs are located strategically along the histone tail as a way for the cell to deal, reversibly, with gene silencing or activation. The lab has been a front-runner in deciphering elaborate interactions within the same histone tails (cis) or across distinct histone tails (trans). These combinatorial changes appear to govern chromatin function in a variety of processes, and have been described as the “histone or epigenetic code” — a widely cited and influential hypothesis.
More recently, researchers in the Allis lab proposed that the mammalian genome is indexed by H3 variants so as to control whether genes are constitutively expressed or remain silent. The Allis lab produced the first genome-wide maps of H3.3 localization, first in mammalian embryonic stem cells and then again after the cells had differentiated to become neurons. Biochemical approaches have led to chaperone complexes that engage H3.3 selectively, depositing it into distinct regions of the genome. One of these chaperone systems is mutated in a significant fraction of patients who suffer from pancreatic neuroendocrine tumors, and H3.3 mutations are also highly specific to pediatric gliomas. Dr. Allis and his colleagues hypothesize these mutations can alter the recruitment and activity of histone-modifying complexes and therefore alter the epigenetic landscape and dysregulate gene expression. Given the restricted distribution of H3.3 mutations to pediatric gliomas, they further hypothesize that cell lineage-specific cellular context is crucial for the ability of these mutations to mediate oncogenesis. Active investigations are under way to test these hypotheses with collaborators in more clinically relevant settings, including human patients.
B.S. in biology, 1973
University of Cincinnati
M.S. in biology, 1975
Ph.D. in biology, 1978
University of Rochester, 1978–1981
Assistant Professor, 1981–1986
Associate Professor, 1986–1989
Baylor College of Medicine
University of Rochester
University of Virginia Health System
The Rockefeller University
Dickson Prize, 2002
Massry Prize, 2003
Wiley Prize, 2004
Canada Gairdner International Award, 2007
ASBMB-Merck Award, 2008
Lewis S. Rosenstiel Award, 2011
Japan Prize, 2014
Charles Leopold-Mayer Prize, 2014
Breakthrough Prize, 2015
National Academy of Sciences
American Academy of Arts and Sciences
French Academy of Sciences
Lewis, P.W. et al. Inhibition of PRC2 activity by gain-of-function mutations in pediatric glioblastoma. Science 340, 867–861 (2013).
Banaszynski, L.A. et al. Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells. Cell 155, 107–120 (2013).
Goldberg, A.D. et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678–691 (2010).
Wang, G.G. et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459, 847–851 (2009).
Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).