Heads of Laboratories
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.
The frequent, high-density posttranslational modifications (PTMs) in histone proteins have lead members of the Allis laboratory to hypothesize that PTMs are located in strategic locations along the histone tail as a way for the cell to deal, reversibly, with gene silencing, or in contrast, gene 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. It appears that these regulatory pathways govern chromatin function during DNA replication and repair, chromosome segregation and chromatin compaction as cells undergo apoptosis. The combinatorial read-out of distinct histone modifications that lead to the specification of unique downstream biological processes has been termed the “histone or epigenetic code” — a widely cited and influential hypothesis.
More recently, 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. Biochemical approaches have led them to chaperone complexes that engage H3.3 selectively, depositing it into distinct regions of the genome. One of these chaperone systems (ATRX/Daxx targeting H3.3 to telomeres and other heterochromatic loci) has been shown to be mutated in a significant fraction of patients who suffer from pancreatic neuroendocrine tumors (PanNETs). Remarkably, H3.3 mutations are also highly specific to pediatric gliomas, a disease that is clinically and molecularly distinct from its adult counterpart. Dr. Allis and his colleagues hypothesize that 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.v
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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