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Heads of Laboratories

Head shot of C. David Allis
C. David Allis, Ph.D.
Tri-Institutional Professor
Joy and Jack Fishman Professor
Laboratory of Chromatin Biology and Epigenetics
C.David.Allis@rockefeller.edu

All the cells in the human body have the same genes, but only a small percentage of genes are active in any given cell at any given time. Allis studies chromatin, the DNA–histone protein complex that packages the genetic information within each cell. Chromatin can facilitate or restrict access to specific genes, and serves as a means of gene regulation that lies outside of the DNA itself—the basis of a principle known as 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, nature has evolved sophisticated mechanisms to alter chromatin, and as a result, to regulate gene expression and other biological processes.

One such mechanism involves the addition or loss of chemical groups. The Allis lab is investigating how covalent histone modifications regulate biological processes in a variety of unicellular and multicellular eukaryotic models. Through enzymatic processes such as acetylation, methylation, phosphorylation, and ubiquitylation, histones are believed to function like master on/off switches that determine whether particular genes are active or inactive. Insights into the mechanisms that turn particular genes on or off could lead to better treatments.

The fact that histone proteins are often subject to frequent, high-density posttranslational modifications (PTMs) hasled members of the Allis lab to hypothesize that PTMs are found in strategic locations 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 cross-talk relationships in the same histone tails (cis) or across distinct histone (trans) tails. Thesecombinatorialchanges appear to govern chromatin function in a variety of processes, and have been termed 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 to control whethergenes are constitutively expressed or remain silent. Using biochemical approaches, the group has identified 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 cancers. H3 mutations are also highly enriched in pediatric gliomas. Allis and his colleagues hypothesize that these so-called oncohistone mutationscan alter the recruitment and activity of histone-modifying and “reader”complexes, and therefore change the epigenetic landscape and gene expression. Recent studies have associated PTM “reader” dysregulation in human leukemia; efforts are in progress to develop new drugs that target this interaction.

Given the restricted distribution of H3 oncohistone mutations to various cancers, the Allis lab further hypothesizes that a cell lineage–specific cellular context is crucial for the ability of these mutations to mediate oncogenesis. Active investigations are underway to test this hypothesis with collaborators in clinically relevant settings, including human patients.


EDUCATION

B.S. in biology, 1973
University of Cincinnati

M.S. in biology, 1975
Ph.D. in biology, 1978
Indiana University 

POSTDOC

University of Rochester, 1978–1981 

POSITIONS

Assistant Professor, 1981–1986
Associate Professor, 1986–1989
Professor, 1989–1990
Baylor College of Medicine

Professor, 1990–1995
Syracuse University

Professor, 1995–1998
University of Rochester

Professor, 1998–2003
University of Virginia Health System

Professor, 2003–
The Rockefeller University

AWARDS

Dickson Prize, 2002

Massry Prize, 2003

Wiley Prize, 2004

Canada Gairdner International Award, 2007

ASMBM-Merick Award, 2008

Lewis S. Rosenstiel Award, 2011

Japan Prize, 2014

Charles Leopold-Mayer Prize, 2014

Breakthrough Prize, 2016

Gruber Genetics Prize, 2016

March of Dimes Prize, 2017

MEMBERSHIPS

National Academy of Sciences
American Academy of Arts and Sciences
French Academy of Sciences

SELECTED PUBLICATIONS

Wan, L. et al. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature 543, 265–269 (2017).

Lu, C. et al. Histone H3K36 mutations promotesarcomagenesis through altered histone methylation landscape. Science 352, 844–849 (2016).

Lewis, P.W. et al. Inhibition of PRC2 activity by gain-of-function mutations in pediatric glioblastoma. Science 340, 867–861 (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).