C. David Allis, Ph.D. (1951-2023)
Joy and Jack Fishman Professor
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 field known as epigenetics.
Chromatin is the physiological template of the human genome. Nature has evolved sophisticated mechanisms to alter it and thereby 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. Disease links, notably cancer, are often linked to alterations in epigenetic regulators, and insights into the mechanisms that turn particular genes on or off could lead to better treatments.
Because histone proteins are often subject to frequent, high-density posttranslational modifications (PTMs), the Allis lab hypothesizes that PTMs are found in strategic locations along the histone tail, allowing the cell to reversibly deal with gene silencing or activation. The lab has been a front-runner in deciphering elaborate crosstalk relationships 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 termed the “histone or epigenetic code,” a widely cited and influential hypothesis.
The Allis lab has also investigated mutations in histone H3 that are highly enriched in pediatric gliomas (including the substitution of H3 lysine 27 for methionine, or H3K27M). The team has shown that these so-called oncohistone mutations can alter the recruitment and activity of histone-modifying complexes, and therefore change the epigenetic landscape and gene expression. Given the restricted distribution of these mutations to pediatric gliomas, the Allis lab further hypothesizes that a cell-lineage specific cellular context is crucial for the ability of these mutations to mediate oncogenesis. In support of this idea, current findings have documented that the substitution of H3 lysine 36 for methionine (H3K36M) impairs the differentiation of mesenchymal progenitor cells and generates a type of tumor called undifferentiated sarcoma in vivo. H3K36M mutations have also been documented in a subset of head and neck squamous cell carcinomas. Studies in the lab are now expanding the landscape of oncohistones to a wide range of diverse tumor types and developmental syndromes.
Another area of focus for the lab involves so-called reader proteins that interpret histone modifications. The team discovered that the protein ENL, a reader of histone acetylation, activates oncogenic gene expression programs in human leukemia. They also showed that recurrent mutations in the YEATS domain of ENL drive the formation of Wilms’ tumor, the most common pediatric kidney cancer. These data suggest that displacing ENL from chromatin may be a promising therapy. 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.