Heads of Laboratories
Tri-Institutional Professor
Joy and Jack Fishman Professor
Laboratory of Chromatin Biology and Epigenetics
C.David.Allis@rockefeller.edu
Although every gene exists within every cell in the human body, only a small percentage of genes is activated in any given cell. To manage this genetic information efficiently, nature has evolved a sophisticated system that facilitates access to specific genes. Dr. Allis studies the DNA-histone protein complex called chromatin, which packages the genetic information that exists within each cell and serves as a means of gene regulation that lies outside of the DNA itself — the basis of epigenetics.
Chromatin is the physiological template of the human genome. Elaborate mechanisms have evolved to introduce meaningful variation into chromatin to alter gene expression and other important biological processes. Three major mechanisms of this are covalent histone modifications, chromatin remodeling by ATP-dependent complexes and use of histone variants.
Dr. Allis and his colleagues hypothesize that distinct patterns of covalent histone modifications form a histone or epigenetic “code” that is read by effector proteins to bring about distinct downstream events. Histone proteins, their posttranslational modifications and the enzyme systems responsible for generating them are highly conserved through evolution. The Allis lab is currently investigating different histone modifications 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.
Research from the Allis lab has shown that a robust “on” mark, H3 lysine 4 trimethylation (H3K4me3), “written” by the human mixed lineage leukemia (MLL) protein and “read” by the nucleosome remodeling complex NURF (nucleosome remodeling factor), engages H3K4me3 using a specific PHD finger in its BPTF subunit. They also showed that the NUP98-PHD fusion protein, which is clinically involved in acute myeloid leukemia in humans, blocks the appropriate silencing of the HoxA9 gene cluster, preventing differentiation and maintaining the stem cell properties of bone marrow progenitor cells. An ongoing collaboration with Dinshaw Patel and colleagues at the Sloan-Kettering Institute has provided new insights into how these modules function in reading the histone code. Current collaborative efforts aim toward understanding the structure and function of other “reading modules” that work together to bind to chromatin targets in a multivalent, cooperative fashion.
Dr. Allis and his colleagues hypothesized — and experimentally verified — that lysine/threonine or lysine/serine pairs act like “binary molecular switches” in modifying histone-effector interactions, one aspect of the proposed histone code. They also observed frequent, high-density posttranslational modifications that they hypothesize are located in strategic locations along the histone tail as a way for the cell to deal, reversibly, with gene silencing or perhaps gene activation. The researchers also have documented cross talk relationships in the same histone tails (cis) or across distinct histone (trans) tails. It appears that these regulatory pathways govern chromatin function during DNA replication and repair, chromosome segregation and chromatin compaction as cells undergo apoptosis.
Studies in budding yeast documented a histone modification pathway associated with RNA polymerase II transcription, whereby ubiquitylation of histone H2B leads to methylation of histone H3 on specific lysine residues. These findings suggest that ubiquitylation of H2B affects transcription elongation and nuclear architecture through its effects on chromatin dynamics.
Researchers in the Allis lab recently proposed that the mammalian genome is indexed by H3 variants in a nonrandom fashion reflecting the assembly mechanisms of dedicated “personalized’’ chaperone proteins and exchange factors that 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. In collaboration with bioinformatics experts at the Albert Einstein College of Medicine, they also found that the location of histone H3.3 throughout the genome changed with stem cell differentiation.
CAREER
Dr. Allis received his Ph.D. in 1978 from Indiana University and performed postdoctoral work with Martin Gorovsky at the University of Rochester. Before he joined Rockefeller in 2003 as the Joy and Jack Fishman Professor and head of laboratory, Dr. Allis held several academic positions, including ones at the Baylor College of Medicine and the University of Virginia Health System.
Dr. Allis is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. Among his many honors are the 2011 Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science, the 2008 ASBMB-Merck Award, the 2007 Gairdner Foundation International Award, the 2004 Wiley Prize in Biomedical Sciences, the 2003 Massry Prize and the 2002 Dickson Prize in Biomedical Sciences.
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