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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) has led 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. These combinatorial changes 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 whether genes 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 mutations can 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.

Allis is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.